Fumarate Ester Pharmaceutical Compositions

ABSTRACT

Described herein are pharmaceutical compositions comprising fumarate esters, methods for making the same, and methods for treating subjects in need thereof. In particular, oral pharmaceutical compositions comprising fumarate esters are described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/730,832, filed on Oct. 12, 2017, which is a divisional of U.S. patentapplication Ser. No. 15/358,349, filed Nov. 22, 2016, which is adivisional of U.S. patent application Ser. No. 15/073,720, filed on Mar.18, 2016, which is a divisional of U.S. patent application Ser. No.14/840,072, filed on Aug. 31, 2015, which is a continuation-in-part ofU.S. patent application Ser. No. 14/633,164, and International PatentApplication No. PCT/US2015/017893, both filed on Feb. 27, 2015, each ofwhich claim priority to U.S. Provisional Patent Application Nos.62/061,185, filed on Oct. 8, 2014, 62/011,604, filed on Jun. 13, 2014,61/950,648, filed on Mar. 10, 2014; and 61/946,233, filed on Feb. 28,2014; and each of which is incorporated herein in its entirety byexpress reference thereto.

TECHNICAL FIELD

Described herein are pharmaceutical compositions comprising fumarateesters, methods for making the same, and methods for treating subjectsin need thereof. In particular, oral pharmaceutical compositionscomprising fumarate esters are described.

BACKGROUND

Fumaric acid esters (FAE; fumarate esters, e.g., alkyl or dialkylfumarate esters such as dimethyl fumarate or monomethyl fumarate) arepharmacologically active substances used for treatinghyperproliferative, inflammatory, or autoimmune disorders. They werefirst used to treat psoriasis and were licensed for this indication inGermany in 1995 as Fumaderm® (Biogen Idec, Inc., Cambridge, Mass., USA).Fumaderm® produces various undesirable side effects, including flushing,headaches, dizziness, eructation, nausea, vomiting, abdominal andintestinal cramps, and diarrhea. High concentrations of the drugreleased in the stomach are believed to be responsible for such sideeffects.

After oral intake, the main component of Fumaderm®, dimethyl fumarate(DMF), is hydrolysed by esterases to monomethyl fumarate (MMF), thebioactive metabolite. After absorption in the small intestine, MMF isbelieved to interact with immunocytes in the bloodstream. The primaryplasma metabolites of DMF are monomethyl fumarate, fumaric acid, citricacid, and glucose. Monomethyl fumarate is further metabolized in thetricarboxylic acid cycle to carbon dioxide and water.

An improved oral formulation of DMF was developed and approved for thetreatment of multiple sclerosis. This formulation, TECFIDERA® (BiogenIdec, Inc.), is available as hard gelatin delayed-release capsulescontaining 120 mg or 240 mg of granulated dimethyl fumarate entericallycoated minitablets. See International Patent Application Publication No.WO 2013/119677 and U.S. Pat. No. 6,509,376. TECFIDERA® was intended toreduce the undesirable side effects by preventing release of DMF in thestomach.

The enterically coated DMF granules in TECFIDERA®, however, lackuniformity in shape and size, and the enteric coating may not be evenlydistributed over the minitablets. This lack of homogeneity can diminishthe enteric properties and affect the acid-resistance, dissolution, andrelease rates. In addition, the integrity of the acid-resistant coatingfails when the coating cracks or flakes off. This leads to DMF releasein the stomach and can cause flushing and the negative gastrointestinalside effects.

A subject's stomach content also affects delivery of DMF fromTECFIDERA®. A meal was shown to decrease C_(max) by 40% and delayT_(max) from 2.0 hours to 5.5 hours; the AUC was unaffected. See WO2006/037342. A reduction in the incidence of flushing by approximately25% in the postprandial state was also observed. See TECFIDERA®Prescribing Information 03/2013 (Biogen Idec Inc.).

In addition, DMF sublimes at relatively low temperatures. About 15-20%of the DMF active ingredient is lost owing to sublimation during thewet-granulation processing used to manufacture TECFIDERA®. See WO2013/076216. Sublimation also causes loss of DMF during storage andunused TECFIDERA® capsules must be discarded 90 days after a bottle ofthe capsules is opened.

Accordingly, it is desirable to develop oral controlled releaseformulations of fumarate esters that: (1) prevent flushing and theundesirable GI side effects associated with oral administration offumarate esters; (2) reduce or eliminate fumarate ester sublimationduring manufacturing and storage; (3) increase the long-term stabilityof the pharmaceutical composition; and (4) provide a variety ofdifferent release profiles, dosage forms, and dosing regimens.

SUMMARY

Described herein are controlled release pharmaceutical compositionscomprising one or more fumarate esters suspended in a lipid orlipophilic matrix. The pharmaceutical composition is encapsulated in anenteric soft capsule. The oral enteric soft capsules comprisingcontrolled release matrix compositions prevent release of the fumarateester active ingredient in the gastric environment, but release theactive ingredient in the intestine in a controlled manner. Thecompositions can be tailored to provide one or more release profiles,including immediate release, controlled release, delayed release, orextended release pharmacokinetics by the composition of the matrix fill.The formulations described herein comprise solid micronized particles offumarate esters suspended in a matrix. The controlled release entericcapsule comprising a matrix of fumarate esters reduce, ameliorate, oreliminate the undesirable gastrointestinal side effects observed withprior fumarate ester pharmaceuticals. Further, the formulations precludeor reduce sublimation of the fumarate ester during manufacturing andstorage.

One embodiment described herein is an oral pharmaceutical compositioncomprising a controlled release composition of one or more fumarateesters, including, but not limited to, dialkyl fumarates, alkylfumarates, dimethyl fumarate (DMF), monomethyl fumarate (MMF), orcombinations thereof. In one embodiment, the pharmaceutical compositioncomprises a controlled release enteric soft capsule shell encapsulatinga matrix comprising one or more fumarate esters. In one aspect, thematrix comprises a lipid or lipophilic vehicle, a neutralizing agent,and solid particles of fumarate esters. In another aspect, the matrixcomprises a lipid or lipophilic vehicle, a neutralizing agent,excipients, and solid particles of a fumarate ester. In another aspect,the matrix comprises a lipid or lipophilic vehicle, a neutralizingagent, surfactants, and solid particles of a fumarate ester. In oneaspect, the lipid or lipophilic vehicle comprises polyvinylpyrrolidones,mono- and di-glycerides, and oils. In another aspect, the surfactant cancomprise polysorbate 80 or polyoxyl 40 hydrogenated castor oil. Inanother aspect, the solid particles of fumarate ester comprise milled ormicronized particles. In another aspect, the milled or micronizedparticles of one or more fumarate esters comprise mean particledistribution sizes of about 20 μm to about 300 μm, including allintegers within the specified range. In another aspect, the solidparticles of fumarate esters comprise mean particle distribution sizesof about 65 μm to about 260 μm, including all integers within thespecified range. In another aspect, the solid microparticles of fumarateesters have mean particle distribution sizes of less than 260 μm. Inanother aspect, the solid particles of fumarate esters have meanparticle distribution sizes of about 100 μm. In another aspect, theneutralizing agent comprises an organic acid, ester, or salt. In anotheraspect, the neutralizing agent comprises at least one of lactate,fumarate, caprylate, caprate, oleate, maleate, succinate, tartrate,citrate, glutamate, gluconate, or esters or salts thereof, orcombinations thereof. In another aspect, the matrix comprises one ormore fumarate esters, a mixture of mono- and di-glycerides,polyvinylpyrrolidone, polyoxyl 40 hydrogenated castor oil, and lacticacid.

In another embodiment, the pharmaceutical composition comprises a matrixfill comprising about 10% to about 64% by weight of one or more fumarateesters (FAE; PSD d90≤100 μm); about 18% to about 70% by weight of amixture of mono- and di-glycerides; at least about 1% to about 10% byweight polyvinylpyrrolidone; at least about 1% to about 10% by weightpolyoxyl 40 hydrogenated castor oil, and at least about 1% to about 5%by weight lactic acid.

In another embodiment, the pharmaceutical composition comprises a matrixfill comprising about 29% by weight of one or more fumarate esters (FAE;PSD d90≤100 μm); about 54% by weight of a mixture of mono- anddi-glycerides; about 3% by weight polyvinylpyrrolidone; about 10% byweight polyoxyl 40 hydrogenated castor oil, and about 5% by weightlactic acid. In one aspect, the composition has controlled release,delayed release, or extended release properties. In one aspect, thecomposition comprises one or more FAEs in an amount of about 80 mg toabout 480 mg. In one aspect, the one or more FAEs comprise about 90 mgto about 120 mg. In one aspect, the composition comprises one or moreFAEs in an amount of about 180 mg to about 240 mg. In one aspect, theone or more FAEs in an amount of about 360 mg to about 480 mg. In oneaspect, the composition comprises one or more FAEs in an amount of about80 mg FAE, about 85 mg FAE, about 90 mg FAE, about 95 mg FAE, about 100mg FAE, about 105 mg FAE, about 110 mg FAE, about 115 mg FAE, about 120mg FAE, about 125 mg FAE, about 130 mg FAE, about 135 mg FAE, about 140mg FAE, about 145 mg FAE, about 150 mg FAE, about 155 mg FAE, about 160mg FAE, about 165 mg FAE, about 170 mg FAE, about 175 mg FAE, about 180mg FAE, about 185 mg FAE, about 190 mg FAE, about 195 mg FAE, about 200mg FAE, about 205 mg FAE, about 210 mg FAE, about 215 mg FAE, about 220mg FAE, about 225 mg FAE, about 230 mg FAE, about 235 mg FAE, about 240mg FAE, about 245 mg FAE, about 250 mg FAE, about 255 mg FAE, about 260mg FAE, about 265 mg FAE, about 270 mg FAE, about 275 mg FAE, about 280mg FAE, about 285 mg FAE, about 290 mg FAE, about 295 mg FAE, about 300mg FAE, about 305 mg FAE, about 310 mg FAE, about 315 mg FAE, about 320mg FAE, about 325 mg FAE, about 330 mg FAE, about 335 mg FAE, about 340mg FAE, about 345 mg FAE, about 350 mg FAE, about 355 mg FAE, about 360mg FAE, about 365 mg FAE, about 370 mg FAE, about 375 mg FAE, about 380mg FAE, about 385 mg FAE, about 390 mg FAE, about 395 mg FAE, about 400mg FAE, about 405 mg FAE, about 410 mg FAE, about 415 mg FAE, about 4 20mg FAE, about 425 mg FAE, about 430 mg FAE, about 435 mg FAE, about 440mg FAE, about 445 mg FAE, about 450 mg FAE, about 455 mg FAE, about 460mg FAE, about 465 mg FAE, about 470 mg FAE, about 475 mg FAE, or about480 mg FAE. In one aspect, the composition comprises one or more FAEs inan amount of about 0.5 mmol to about 4.0 mmol FAE. In another aspect,the composition comprises one or more FAEs in an amount of about 0.7mmol to about 3.7 mmol FAE. In another aspect, the composition comprisesDMF, MMF, or a combination thereof. In another aspect, the compositioncomprises DMF. In another aspect, the composition further comprises oneor more non-steroidal anti-inflammatory drugs (NSAIDS). In one aspect,the composition prevents sublimation of the fumarate ester duringmanufacturing. In another aspect, the composition prophylacticallyreduces the onset or ameliorates the symptoms of any flushing sideeffects. In another aspect, the composition reduces the onset orameliorates the severity of any gastrointestinal side effects. Inanother aspect, the composition is stable for at least 1 year atconditions comprising 25° C. and 60% relative humidity. In anotheraspect, the composition is stable for at least 2 years at conditionscomprising 25° C. and 60% relative humidity.

In one embodiment, the enteric soft capsule shell comprises one or moreenteric, acid-insoluble polymers, and in a preferred embodimentadditionally includes a film-forming polymer, a plasticizer, analkali-neutralizing agent, a solvent, and optionally, a coloring agent,a flavoring, or a pharmaceutical excipient.

In another embodiment, the enteric soft capsule shell comprises about20% to about 36% by weight of at least one film-forming polymer; about8% to about 20% by weight of at least one enteric, acid-insolublepolymer; about 15% to about 20% by weight of at least one plasticizer;about 1% to about 5% by weight of at least one alkali-neutralizingagent; about 20% to about 40% by weight of a solvent; optionally, about1% to about 5% by weight of an opacifying agent; and optionally, about0.05% to about 1% by weight of at least one coloring agent.

In another embodiment, the enteric soft capsule shell comprises about30% of at least one film-forming polymer; about 10% by weight of atleast one enteric, acid-insoluble polymer; about 20% by weight of atleast one plasticizer; about 1% by weight of at least onealkali-neutralizing agent; about 37% by weight of a solvent; andoptionally, about 1.5% by weight of an opacifying agent; and optionally,at least one coloring agent. In one aspect, the enteric soft capsuleshell comprises gelatin, acrylic methacrylate copolymers, glycerol,triethyl citrate, ammonia, water, and titanium dioxide.

Another embodiment described herein is a method for manufacturing anoral enteric soft capsule shell encapsulating a matrix comprising afumarate ester, the method comprising: (i) providing a matrix fillcomposition comprising any of the composition described herein; (ii)providing an enteric soft capsule shell composition comprising any ofthe composition described herein; (iii) casting the enteric soft capsuleshell into films using heat-controlled drums or surfaces; and (iv)forming an enteric soft capsule shell encapsulating the matrix fillcomposition using rotary die encapsulation technology. In one aspect,the enteric soft capsule matrix comprises one or more fumarate estersproduced by said method.

Another embodiment described herein is a method for manufacturing anoral enteric soft capsule shell encapsulating a matrix comprising afumarate ester, the method comprising: (i) providing a matrix fillcomposition comprising: about 10% to about 64% by weight of one or morefumarate esters (FAE; PSD d90≤100 μm); about 18% to about 70% by weightof a mixture of mono- and di-glycerides; about 1% to about 10% by weightpolyvinylpyrrolidone; about 2% to about 12% by weight polyoxyl 40hydrogenated castor oil, and about 1% to about 5% by weight lactic acid;(ii) providing an enteric soft capsule shell composition comprising:about 20% to about 36% by weight of at least one film-forming polymer;about 8% to about 20% by weight of at least one enteric, acid-insolublepolymer; about 15% to about 20% by weight of at least one plasticizer;about 1% to about 5% by weight of at least one alkali-neutralizingagent; about 20% to about 40% by weight of a solvent; optionally, about1% to about 5% by weight of an opacifying agent; and optionally, about0.05% to about 1% by weight of at least one coloring agent; (iii)casting the enteric soft capsule shell into films using heat-controlleddrums or surfaces; and (iv) forming an enteric soft capsule shellencapsulating the matrix fill composition using rotary die encapsulationtechnology.

Another embodiment described herein is an enteric soft capsulecomprising a shell encapsulating a fumarate ester matrix, wherein thematrix comprises: about 10% to about 64% by weight of one or morefumarate esters (FAE; PSD: <100 μm); about 18% to about 70% by weight ofmono- and di-glycerides; at least about 1% to about 7% by weight ofpolyvinylpyrrolidone; at least about 2% to about 10% by weight ofpolyoxyl 40 hydrogenated castor oil, and at least about 1% to about 5%by weight of lactic acid; and wherein the enteric soft capsule shellcomprises: about 20% to about 36% by weight of at least one film-formingpolymer; about 8% to about 20% by weight of at least one enteric,acid-insoluble polymer; about 15% to about 20% by weight of at least oneplasticizer; about 1% to about 5% by weight of at least onealkali-neutralizing agent; about 20% to about 40% by weight of asolvent; optionally, about 1% to about 5% by weight of an opacifyingagent; and optionally, about 0.05% to about 1% by weight of at least onecoloring agent.

Another embodiment described herein is an enteric soft capsulecomprising a shell encapsulating a fumarate ester matrix, wherein thematrix comprises: about 29% by weight of one or more fumarate esters(FAE; PSD d90≤100 μm); about 54% by weight of a mixture of mono- anddi-glycerides; about 3% by weight polyvinylpyrrolidone; about 10% byweight polyoxyl 40 hydrogenated castor oil, and about 5% by weightlactic acid; and wherein the enteric soft capsule shell comprises: about30% by weight of at least one film-forming polymer; about 10% by weightof at least one enteric, acid-insoluble polymer; about 20% by weight ofat least one plasticizer; about 1% by weight of at least onealkali-neutralizing agent; about 37% by weight of a solvent; optionally,about 1.5% by weight of an opacifying agent; and optionally, at leastone coloring agent. In another aspect, the composition comprises DMF,MMF, or a combination thereof. In another aspect, the compositioncomprises DMF. In one aspect, the enteric soft capsule comprising afumarate ester is resistant to dissolution at about pH 1.2 for at leastabout 2 hours. In another aspect, the enteric soft capsule comprising afumarate ester begins dissolution at pH of about 6.8 within about 10minutes. In one aspect, the enteric soft capsule has immediate release,controlled release, delayed release, or extended release properties. Inanother aspect, the enteric soft capsule comprising a fumarate esterreduces the onset or ameliorates the severity of any flushing orgastrointestinal side effects.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of multiple sclerosis or psoriasis,comprising administering to a subject in need thereof an oralpharmaceutical composition comprising a controlled release enteric softcapsule shell and matrix comprising a fumarate ester. In one aspect, thepharmaceutical composition comprises a controlled release enteric softcapsule comprising a formulation of fumarate ester. In another aspect,the composition comprises DMF, MMF, or a combination thereof. In anotheraspect, the composition comprises DMF.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising administering to a subject in needthereof an oral pharmaceutical composition comprising a controlledrelease formulation of a fumarate ester, wherein the subject achieves areduction of annualized relapse rate relative to baseline withoutsubstantially experiencing one or more of flushing, abdominal pain,diarrhea, and nausea. In one aspect, the pharmaceutical compositioncomprises any of the compositions described herein. In another aspect,the composition comprises DMF, MMF, or a combination thereof. In anotheraspect, the composition comprises DMF.

Another embodiment described herein is an oral pharmaceuticalcomposition as described herein that is useful for treatingneurodegenerative disorders. In one aspect, the pharmaceuticalcomposition is useful for treating multiple sclerosis or psoriasis. Inone embodiment described herein, subjects that are administered the oralpharmaceutical composition as described herein exhibit a mean plasmamonomethyl fumarate T_(max) of from about 1.5 hours to about 3.5 hours.

Another embodiment described herein is an oral pharmaceuticalcomposition useful for treating, retarding the progression of, delayingthe onset of, prophylaxis of, amelioration of, or reducing the symptomsof general autoimmune or neurodegenerative disorders. In another aspect,the composition comprises DMF, MMF, or a combination thereof. In anotheraspect, the composition comprises DMF.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of general autoimmune or neurodegenerativedisorders. In another aspect, the composition comprises DMF, MMF, or acombination thereof. In another aspect, the composition comprises DMF.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a controlled release composition comprising aformulation of a fumarate ester useful for treating, retarding theprogression of, delaying the onset of, prophylaxis of, amelioration of,or reducing the symptoms of general autoimmune or neurodegenerativedisorders, including but not limited to, acute dermatitis, adrenalleukodystrophy, AGE-induced genome damage, Alexander's disease, alopeciaareata (totalis and universalis), Alper's disease, Alzheimer's disease,amyotrophic lateral sclerosis, angina pectoris, arthritis, asthma,autoimmune diseases, balo concentric sclerosis, Behcet's syndrome,bullous pemphigoid, Canavan disease, cardiac insufficiency includingleft ventricular insufficiency, central nervous system vasculitis,Charcot-Marie-Tooth disease, childhood ataxia with central nervoussystem hypomyelination, chronic active (lupoid) hepatitis, chronicdermatitis, chronic idiopathic peripheral neuropathy, chronicobstructive pulmonary disease, contact dermatitis, Crohn's disease andcutaneous Crohn's disease, cutaneous lupus, cutaneous sarcoidosis,diabetic retinopathy, fibromyalgia, graft versus host disease, granulomaannulare, granulomas including annulare, Grave's disease, Hashimoto'sthyroiditis, hepatitis C viral infection, herpes simplex viralinfection, human immunodeficiency viral infection, Huntington's disease,inflammatory bowel disease, irritable bowel disorder, ischemia,juvenile-onset diabetes mellitus, Krabbe disease, lichen planus, maculardegeneration, mitochondrial encephalomyopathy, monomelic amyotrophy,multiple sclerosis (MS), myocardial infarction, necrobiosis lipoidica,neurodegeneration with brain iron accumulation, neurodermatitis,neuromyelitis optica, neuropathic pain, neurosarcoidosis, NF-κB mediateddiseases, optic neuritis, organ transplantation rejection,paraneoplastic syndromes, Parkinson's disease, Pelizaeus-Merzbacherdisease, pemphigus, pernicious anemia, primary lateral sclerosis,progressive supranuclear palsy, psoriasis, psoriatic arthritis, pyodermagangrenosum, radicular pain, radiculopathic pain, reperfusion injury,retinopathic pigmentosa, rheumatoid arthritis (RA), sarcoidosis,sarcoidosis, Schilder's disease, sciatic pain, sciatica, Sjögren'ssyndrome, subacute necrotizing myelopathy, such as polyarthritis,Susac's syndrome, systemic lupus erythematosus (SLE), tumors, transversemyelitis, ulcerative colitis, or Zellweger syndrome. In another aspect,the composition comprises DMF, MMF, or a combination thereof. In anotheraspect, the composition comprises DMF.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of general autoimmune or neurodegenerativedisorders, including but not limited to, acute dermatitis, adrenalleukodystrophy, AGE-induced genome damage, Alexander's disease, alopeciaareata (totalis and universalis), Alper's disease, Alzheimer's disease,amyotrophic lateral sclerosis, angina pectoris, arthritis, asthma,autoimmune diseases, balo concentric sclerosis, Behcet's syndrome,bullous pemphigoid, Canavan disease, cardiac insufficiency includingleft ventricular insufficiency, central nervous system vasculitis,Charcot-Marie-Tooth disease, childhood ataxia with central nervoussystem hypomyelination, chronic active (lupoid) hepatitis, chronicdermatitis, chronic idiopathic peripheral neuropathy, chronicobstructive pulmonary disease, contact dermatitis, Crohn's disease andcutaneous Crohn's disease, cutaneous lupus, cutaneous sarcoidosis,diabetic retinopathy, fibromyalgia, graft versus host disease, granulomaannulare, granulomas including annulare, Grave's disease, Hashimoto'sthyroiditis, hepatitis C viral infection, herpes simplex viralinfection, human immunodeficiency viral infection, Huntington's disease,inflammatory bowel disease, irritable bowel disorder, ischemia,juvenile-onset diabetes mellitus, Krabbe disease, lichen planus, maculardegeneration, mitochondrial encephalomyopathy, monomelic amyotrophy,multiple sclerosis (MS), myocardial infarction, necrobiosis lipoidica,neurodegeneration with brain iron accumulation, neurodermatitis,neuromyelitis optica, neuropathic pain, neurosarcoidosis, NF-κB mediateddiseases, optic neuritis, organ transplantation rejection,paraneoplastic syndromes, Parkinson's disease, Pelizaeus-Merzbacherdisease, pemphigus, pernicious anemia, primary lateral sclerosis,progressive supranuclear palsy, psoriasis, psoriatic arthritis, pyodermagangrenosum, radicular pain, radiculopathic pain, reperfusion injury,retinopathic pigmentosa, rheumatoid arthritis (RA), sarcoidosis,sarcoidosis, Schilder's disease, sciatic pain, sciatica, Sjögren'ssyndrome, subacute necrotizing myelopathy, such as polyarthritis,Susac's syndrome, systemic lupus erythematosus (SLE), tumors, transversemyelitis, ulcerative colitis, or Zellweger syndrome comprisingadministering to a subject in need thereof an oral controlled releasepharmaceutical composition comprising a fumarate ester. In oneembodiment described herein, the oral pharmaceutical compositioncomprises an enteric soft capsule shell and matrix comprising a fumarateester. In one aspect, the pharmaceutical composition comprises acontrolled release enteric soft capsule comprising a formulation of afumarate ester. In another aspect, the pharmaceutical composition is animmediate release, delayed release, controlled release, or extendedrelease formulation of a fumarate ester. In another aspect, thecomposition comprises DMF, MMF, or a combination thereof. In anotheraspect, the composition comprises DMF.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a controlled release formulation of a fumarateester. In one aspect, the composition is provided in a dosage formcontaining about 80 mg to about 120 mg of one or more fumarate esters,wherein subjects administered the dosage form four times daily exhibitone or more pharmacokinetic parameters comprising: (a) a mean plasmamonomethyl fumarate C_(max) ranging from about 0.4 mg/L to about 2.41mg/L; or (b) a mean plasma monomethyl fumarate AUC_(overall) rangingfrom about 3.2 h·mg/L to about 11.2 h·mg/L. In another aspect, thecomposition is provided in a dosage form containing about 120 mg toabout 180 mg of one or more fumarate esters, wherein subjectsadministered the dosage form exhibit one or more pharmacokineticparameters comprising: (a) a mean plasma monomethyl fumarate C_(max)ranging from about 0.4 mg/L to about 2.41 mg/L; (b) a mean plasmamonomethyl fumarate AUC_(0→12h) ranging from about 0.5 h·mg/L to about2.5 h·mg/L; or (c) a mean AUC_(0→∞) ranging from about 0.5 h·mg/L toabout 2.6 h·mg/L. In another aspect, the composition is provided in adosage form containing a total amount of about 180 mg to about 240 mg ofone or more fumarate esters, wherein subjects administered the dosageform twice-daily exhibit one or more pharmacokinetic parameterscomprising: (a) a mean plasma monomethyl fumarate C_(max) ranging fromabout 1.0 mg/L to about 3.4 mg/L; (b) a mean plasma monomethyl fumarateAUC_(overall) ranging from about 4.81 h·mg/L to about 11.2 h·mg/L. Inanother aspect, the composition is provided in a dosage form containingabout 180 mg to about 240 mg of one or more fumarate esters, whereinsubjects administered the dosage form exhibit one or morepharmacokinetic parameters comprising: (a) a mean plasma monomethylfumarate C_(max) ranging from about 1.0 mg/L to about 3.4 mg/L; (b) amean plasma monomethyl fumarate AUC_(0→42h) ranging from about 1.0h·mg/L to about 5.5 h·mg/L; or (c) a mean AUC_(0→∞) ranging from about1.0 h·mg/L to about 5.6 h·mg/L. In another aspect, the fumarate esterformulation is encapsulated in an enteric soft capsule. In anotheraspect, the composition comprises DMF, MMF, or a combination thereof. Inanother aspect, the composition comprises DMF.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising total amount of about 80 mg to about 120 mg ofone or more fumarate esters, wherein subjects administered the capsuleexhibit one or more pharmacokinetic parameters comprising: (a) a meanplasma monomethyl fumarate T_(max) of from about 1.5 hours to about 3.5hours; (b) a mean plasma monomethyl fumarate C_(max) ranging from about0.4 mg/L to about 2.41 mg/L; (c) a mean plasma monomethyl fumarateAUC_(0→12h) ranging from about 0.5 h·mg/L to about 2.5 h·mg/L; or (d) amean AUC_(0→∞) ranging from about 0.5 h·mg/L to about 2.6 h·mg/L. Inanother aspect, the composition comprises about 180 mg to about 240 mgof one or more fumarate esters, wherein subjects administered thecapsule exhibit one or more pharmacokinetic parameters comprising: (a) amean plasma monomethyl fumarate T_(max) of from about 1.5 hours to about3.5 hours; (b) a mean plasma monomethyl fumarate C_(max) ranging fromabout 1.0 mg/L to about 3.4 mg/L; (c) a mean plasma monomethyl fumarateAUC_(0→12h) ranging from about 1.0 h·mg/L to about 5.5 h·mg/L; or (d) amean AUC_(0→∞) ranging from about 1.0 h·mg/L to about 5.6 h·mg/L. In oneaspect, the composition comprises DMF, MMF, or a combination thereof. Inanother aspect, the composition comprises DMF.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising orally administering to a subject inneed thereof a therapeutically effective amount of one or more fumarateesters comprising any of the compositions described herein and atherapeutically amount of one or more non-steroidal anti-inflammatorydrugs effective to reduce flushing. In one aspect, the one or morenon-steroidal anti-inflammatory drug is aspirin, ibuprofen, naproxene,diclofenac, ketoprofen, celecoxib, or a combination thereof.

Another embodiment described herein is a once or twice daily oralpharmaceutical composition comprising a delayed release, controlledrelease, or extended release formulation of a fumarate ester. In oneaspect, the composition is provided in one or more dosage formscontaining about 80 mg to about 480 mg of one or more fumarate esters,wherein subjects administered the dosage form once daily exhibit one ormore pharmacokinetic parameters comprising: (a) a mean plasma monomethylfumarate C_(max) ranging from about 0.4 mg/L to about 5.2 mg/L; or (b) amean plasma monomethyl fumarate AUC_(0→∞) ranging from about 0.5 h·mg/Lto about 15.5 h·mg/L. In another aspect, the composition is provided inone or more dosage forms containing about 80 mg to about 480 mg of oneor more fumarate esters, wherein subjects administered the dosage formonce daily exhibit one or more pharmacokinetic parameters comprising:(a) a mean plasma monomethyl fumarate C_(max) ranging from about 0.4mg/L to about 5.2 mg/L, (b) a mean plasma monomethyl fumarateAUC_(0→12h) ranging from about 0.5 h·mg/L to about 13.5 h·mg/L, or (c) amean AUC_(0→∞) ranging from about 0.5 h·mg/L to about 15.5 h·mg/L. Inanother aspect, the capsule contains a total amount of about 80 mg toabout 480 mg of one or more fumarate esters, wherein subjectsadministered the one or more capsules exhibit one or morepharmacokinetic parameters comprising: (a) a mean plasma monomethylfumarate T_(max) of from about 1.5 hours to about 10.5 hours; (b) a meanplasma monomethyl fumarate C_(max) ranging from about 0.4 mg/L to about5.2 mg/L; (c) a mean plasma monomethyl fumarate AUC_(0→42h) ranging fromabout 0.5 h·mg/L to about 13.5 h·mg/L; or (d) a mean AUC_(0→∞) rangingfrom about 0.5 h·mg/L to about 15.5 h·mg/L.

Another embodiment described herein is a pharmaceutical composition asdescribed herein, for oral administration to a subject having multiplesclerosis containing one or more fumarate ester compounds, orpharmaceutically acceptable salts thereof that metabolize to monomethylfumarate, wherein said administering the composition provides one ormore of the following pharmacokinetic parameters: (a) a mean plasmamonomethyl fumarate T_(max) of from about 1.5 hours to about 3.5 hours;(b) a mean plasma monomethyl fumarate C_(max) ranging from about 0.4mg/L to about 3.4 mg/L; (c) a mean plasma monomethyl fumarateAUC_(overall) ranging from about 3.2 h·mg/L to about 11.2 h·mg/L; (d) amean plasma monomethyl fumarate AUC_(0→12h) ranging from about 0.5h·mg/L to about 5.5 h·mg/L; or (e) a mean AUC_(0→∞) ranging from about0.5 h·mg/L to about 5.6 h·mg/L.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising administering to a subject in needthereof any one of the compositions of described herein, containing oneor more fumarate ester compounds, or pharmaceutically acceptable saltsthereof that metabolize to monomethyl fumarate, wherein saidadministering the composition provides one or more of the followingpharmacokinetic parameters: (a) a mean plasma monomethyl fumarateT_(max) of from about 1.5 hours to about 3.5 hours; (b) a mean plasmamonomethyl fumarate C_(max) ranging from about 0.4 mg/L to about 3.4mg/L; (c) a mean plasma monomethyl fumarate AUC_(overall) ranging fromabout 3.2 h·mg/L to about 11.2 h·mg/L; (d) a mean plasma monomethylfumarate AUC_(0→12h) ranging from about 0.5 h·mg/L to about 5.5 h·mg/L;or (e) a mean AUC_(0→∞) ranging from about 0.5 h·mg/L to about 5.6h·mg/L.

Another embodiment described herein is a pharmaceutical composition asdescribed herein, for oral administration to a subject having multiplesclerosis containing one or more fumarate ester compounds, orpharmaceutically acceptable salts thereof that metabolize to monomethylfumarate, wherein said administering the composition provides one ormore of the following pharmacokinetic parameters: (a) a mean plasmamonomethyl fumarate T_(max) of from about 1.5 hours to about 10.5 hours;(b) a mean plasma monomethyl fumarate C_(max) ranging from about 0.4mg/L to about 5.2 mg/L; (c) a mean plasma monomethyl fumarateAUC_(0→42h) ranging from about 0.5 h·mg/L to about 13.5 h·mg/L; or (d) amean AUC_(0→∞) ranging from about 0.5 h·mg/L to about 15.5 h·mg/L.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising orally administering to a subject inneed thereof any one of the compositions described herein comprising oneor more fumarate ester compounds, or pharmaceutically acceptable saltsthereof that metabolize to monomethyl fumarate, wherein saidadministering the composition provides one or more of the followingpharmacokinetic parameters: (a) a mean plasma monomethyl fumarateT_(max) of from about 1.5 hours to about 10.5 hours; (b) a mean plasmamonomethyl fumarate C_(max) ranging from about 0.4 mg/L to about 5.2mg/L; (c) a mean plasma monomethyl fumarate AUC_(overall) ranging fromabout 0.5 h·mg/L to about 15.2 h·mg/L; (d) a mean plasma monomethylfumarate AUC_(0→12h) ranging from about 0.5 h·mg/L to about 13.5 h·mg/L;or (e) a mean AUC_(0→∞) ranging from about 0.5 h·mg/L to about 15.5h·mg/L. In one aspect, the composition comprises DMF, MMF, or acombination thereof. In another aspect, the composition comprises DMF.

Another embodiment described herein is a pharmaceutical compositioncomprising any one of the pharmaceutical compositions described hereinfor oral administration to a subject having multiple sclerosis,comprising a therapeutically effective amount of one or more fumarateesters, wherein the administration is sufficient to achieve a reductionof about 0.224 annualized relapse rate relative to baseline in thesubject without substantially inducing one or more of flushing,abdominal pain, diarrhea, and nausea in the subject. In one aspect, thesubject experiences one or more of flushing, abdominal pain, diarrhea,and nausea at a rate of less than about 10%. In another aspect, thesubject is a child. In one aspect, the child is over 9 years of age.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of multiple sclerosis, the methodcomprising the oral administration of a therapeutically effective amountof one or more fumarate esters comprising any one of the pharmaceuticalcompositions described herein, to a subject with multiple sclerosis,wherein the administration is sufficient to achieve a reduction of about0.224 annualized relapse rate relative to baseline in the subjectwithout substantially inducing one or more of flushing, abdominal pain,diarrhea, and nausea in the subject. In one aspect, the subjectexperiences one or more of flushing, abdominal pain, diarrhea, andnausea at a rate of less than about 10%. In another aspect, the subjectis a child. In one aspect, the child is over 9 years of age.

Another embodiment described herein is a pharmaceutical compositioncomprising any one of the pharmaceutical compositions described hereinfor oral administration to a subject having multiple sclerosis,comprising a therapeutically effective amount of one or more fumarateesters, wherein the administration is sufficient to achieve a reductionof annualized relapse rate relative to baseline in the subject withoutsubstantially inducing one or more of flushing, abdominal pain,diarrhea, and nausea in the subject. In one aspect, the subjectexperiences one or more of flushing, abdominal pain, diarrhea, andnausea at a rate of less than about 10%. In another aspect, the subjectis a child. In one aspect, the child is over 9 years of age.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, the method comprising the oral administration ofa therapeutically effective amount of one or more fumarate esterscomprising any one of the pharmaceutical compositions described hereinto a subject in need thereof, wherein the subject achieves a reductionannualized relapse rate relative to baseline without substantiallyexperiencing one or more of flushing, abdominal pain, diarrhea, andnausea. In one aspect, the subject experiences one or more of flushing,abdominal pain, diarrhea, and nausea at an incidence rate of less thanabout 10%. In another aspect, the subject is a child. In one aspect, thechild is over 9 years of age.

Another embodiment described herein is a pharmaceutical compositioncomprising any one of the pharmaceutical compositions described herein,for oral administration to a subject having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis, comprising a therapeutically effective amount of one or morefumarate esters, wherein the administration is sufficient to achieve areduction of annualized relapse rate relative to baseline in the subjectwithout substantially inducing one or more of flushing, abdominal pain,diarrhea, and nausea in the subject; and wherein the administration doesnot require titration of the pharmaceutical composition. In one aspect,the subject experiences one or more of flushing, abdominal pain,diarrhea, and nausea at an incidence rate of less than about 10%. Inanother aspect, the subject is a child. In one aspect, the child is over9 years of age.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis, the method comprising the oral administration of atherapeutically effective amount of one or more fumarate esterscomprising any one of the pharmaceutical compositions described herein,to a subject in need thereof, wherein the administration is sufficientto achieve a reduction of annualized relapse rate relative to baselinein the subject without substantially inducing one or more of flushing,abdominal pain, diarrhea, and nausea in the subject; and wherein theadministration does not require titration of the pharmaceuticalcomposition.

Another embodiment described herein is a pharmaceutical compositioncomprising any of the pharmaceutical compositions described herein fororal administration to a subject having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis, comprising a therapeutically effective amount of one or morefumarate esters, wherein the administration is sufficient to achieve areduction of about 0.224 annualized relapse rate relative to baseline inthe subject without substantially inducing one or more of flushing,abdominal pain, diarrhea, and nausea in the subject and wherein theadministration does not require titration of the pharmaceuticalcomposition. In one aspect, the subject experiences one or more offlushing, abdominal pain, diarrhea, and nausea at a rate of less thanabout 10%. In another aspect, the subject is a child. In one aspect, thechild is over 9 years of age.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis, the method comprising the oral administration of atherapeutically effective amount of one or more fumarate esterscomprising any of the pharmaceutical compositions described herein to asubject in need thereof, wherein the administration is sufficient toachieve a reduction of about 0.224 annualized relapse rate relative tobaseline in the subject without substantially inducing one or more offlushing, abdominal pain, diarrhea, and nausea in the subject andwherein the administration does not require titration of thepharmaceutical composition. In one aspect, the subject experiences oneor more of flushing, abdominal pain, diarrhea, and nausea at anincidence rate of less than about 10%. In another aspect, the subject isa child. In one aspect, the child is over 9 years of age.

Another embodiment described herein is a pharmaceutical compositioncomprising any one of the pharmaceutical compositions described herein,for oral administration to a subject having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising a therapeutically effective amount ofone or more fumarate esters, wherein the subject achieves a reduction ofannualized relapse rate relative to baseline without substantiallyexperiencing one or more of flushing, abdominal pain, diarrhea, andnausea in the subject and wherein the administration does not requiretitration of the pharmaceutical composition.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, the method comprising the oral administration ofa therapeutically effective amount of one or more fumarate esterscomprising any one of the pharmaceutical compositions described herein,to a subject in need thereof, wherein the subject achieves a reductionof annualized relapse rate relative to baseline without substantiallyexperiencing one or more of flushing, abdominal pain, diarrhea, andnausea in the subject and wherein the administration does not requiretitration of the pharmaceutical composition.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising any of the compositions described herein foradministration to a subject having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising a therapeutically effective amount ofone or more fumarate esters, wherein the pharmaceutical composition isstable at 25° C. and 60% RH for at least 1 year.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising any of the compositions described hereincomprising a therapeutically effective amount of one or more fumarateesters for administration to a subject diagnosed with multiple sclerosisor psoriasis.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising orally administering to a subject inneed thereof a therapeutically effective amount of one or more fumarateesters comprising any of the pharmaceutical compositions describedherein.

Another embodiment described herein is a pharmaceutical compositioncomprising any one of the compositions described herein, for oraladministration to a subject of less than 17 years of age having ageneral autoimmune or neurodegenerative disorder, including but notlimited to multiple sclerosis or psoriasis, comprising a therapeuticallyeffective amount of one or more fumarate esters.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a subject of less than 17 years of agehaving a general autoimmune or neurodegenerative disorder, including butnot limited to multiple sclerosis or psoriasis, comprising orallyadministering to a subject in need thereof having an age less than 17 atherapeutically effective amount of one or more fumarate esterscomprising any one of the pharmaceutical compositions described herein.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising orally administering to a subject inneed thereof a therapeutically effective amount of a fumarate estercomprising any of the pharmaceutical compositions described herein and atherapeutically effective amount of a leukotriene receptor antagonist.In one aspect, the leukotriene receptor antagonist comprises montelukastor zafirlukast.

Another embodiment described herein is a pharmaceutical compositioncomprising a matrix fill comprising any of the compositions describedherein in Tables 1, 2, 5-24, and 26-28.

Another embodiment described herein is a pharmaceutical composition fortreating, retarding the progression of, delaying the onset of,prophylaxis of, amelioration of, or reducing the symptoms of a generalautoimmune or neurodegenerative disorder, including but not limited tomultiple sclerosis or psoriasis, comprising a fumarate ester, whereinthe pharmaceutical composition exhibits an in vitro dissolution rate (%dissolution per minute) at pH 6.8, as shown in any of Drawings 2-14described herein.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, comprising orally administering to a subject inneed thereof a therapeutically effective amount of one or more fumarateesters comprising any of the pharmaceutical compositions describedherein, wherein the composition exhibits an in vitro dissolution rate (%dissolution per minute) at pH 6.8, as shown in any of Drawings 2-14described herein.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating, retarding the progression of, delaying theonset of, prophylaxis of, amelioration of, or reducing the symptoms ofgeneral autoimmune or neurodegenerative disorders, including but notlimited to multiple sclerosis or psoriasis, comprising one or morefumarate esters, wherein the pharmaceutical composition exhibits aplasma monomethyl fumarate C_(max) of about 1321.3±618.9 ng/mL.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of general autoimmune or neurodegenerativedisorders, including but not limited to multiple sclerosis or psoriasis,comprising orally administering to a subject in need thereof atherapeutically effective amount of one or more fumarate esterscomprising any of the pharmaceutical compositions described herein,wherein the pharmaceutical composition exhibits a plasma monomethylfumarate C_(max) of about 1321.3±618.9 ng/mL.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating, retarding the progression of, delaying theonset of, prophylaxis of, amelioration of, or reducing the symptoms ofgeneral autoimmune or neurodegenerative disorders, including but notlimited to multiple sclerosis or psoriasis, comprising one or morefumarate esters, wherein the pharmaceutical composition exhibits aplasma monomethyl fumarate C_(max) as shown herein in Drawing 15.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of general autoimmune or neurodegenerativedisorders, including but not limited to multiple sclerosis or psoriasis,comprising orally administering to a subject in need thereof atherapeutically effective amount of one or more fumarate esterscomprising any of the pharmaceutical compositions described herein,wherein the pharmaceutical composition exhibits a plasma monomethylfumarate C_(max) as shown herein in Drawing 15.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating, retarding the progression of, delaying theonset of, prophylaxis of, amelioration of, or reducing the symptoms of ageneral autoimmune or neurodegenerative disorder, including but notlimited to multiple sclerosis or psoriasis, comprising one or morefumarate esters, wherein the pharmaceutical composition exhibits an invitro dissolution rate at pH 6.8 comprising about 10% to about 80%dissolution after about 10 minutes to about 480 minutes.

Another embodiment described herein is a method for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of general autoimmune or neurodegenerativedisorders, including but not limited to multiple sclerosis or psoriasis,comprising orally administering to a subject in need thereof atherapeutically effective amount of one or more fumarate esterscomprising any of the pharmaceutical compositions described herein,wherein the pharmaceutical composition is administered without titrationof the pharmaceutical composition and without substantially inducing oneor more of flushing, abdominal pain, diarrhea, and nausea in thesubject.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating, retarding the progression of, delaying theonset of, prophylaxis of, amelioration of, or reducing the symptoms ofgeneral autoimmune or neurodegenerative disorders, comprising one ormore fumarate esters, wherein the pharmaceutical composition isadministered without titration of the pharmaceutical composition andwithout substantially inducing one or more of flushing, abdominal pain,diarrhea, and nausea in the subject.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a controlled release enteric soft capsule shellencapsulating a matrix comprising: about 10% to about 64% by weight ofone or more fumarate esters (FAE; PSD d90≤100 μm); about 18% to about70% by weight of a mixture of mono- and di-glycerides; about 3% byweight of polyvinylpyrrolidone; about 10% by weight of polyoxyl 40hydrogenated castor oil, and about 5% by weight of lactic acid. In oneaspect, the matrix comprises about 13% to about 16%; about 27% to about32%; or about 53% to about 64%, each by weight of one or more FAEs. Inanother aspect, the mixture of mono- and di-glycerides is present in anamount of about 66% to about 69%; about 50% to about 55%; or about 18%to about 29%, each by weight. In another aspect, the one or more FAEscomprise about 80 mg to about 480 mg FAE. In another aspect, the matrixcomprises about 80 mg to about 105 mg FAE, about 90 mg to about 110 mgFAE, about 95 mg to about 115 mg FAE, about 100 mg to about 120 mg FAE;about 180 mg to about 230 mg FAE; about 200 mg to about 240 mg FAE;about 270 mg to about 360 mg FAE; about 360 mg to about 480 mg FAE; orabout 400 to about 480 mg FAE. In another aspect, the matrix comprisesabout 90 mg to about 120 mg FAE. In another aspect, the matrix comprisesabout 180 mg to about 230 mg FAE. In another aspect, the matrixcomprises about 200 mg to about 220 mg FAE. In another aspect, thematrix comprises about 215 mg FAE. In another aspect, the matrixcomprises about 0.5 to about 3.5 mmol FAE. In another aspect, the matrixcomprises about 0.6 to about 1.7 mmol FAE. In another aspect, the matrixcomprises DMF, MMF, or a combination thereof. In another aspect, thematrix comprises DMF.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of a composition comprising one or morefumarate esters in an amount of about 90 mg to about 120 mg FAE or about180 mg to about 240 mg FAE, wherein the one or more doses comprise acontrolled release pharmaceutical composition that releases the contentsat a physiological pH of about pH 6.8.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of one or more fumarate esterscomprising about 90 mg to about 120 mg FAE or about 180 mg to about 240mg FAE wherein the FAE comprises a prodrug of methyl hydrogen fumarateor methyl hydrogen fumarate.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of one or more fumarate esters whereinmethyl hydrogen fumarate activates a nuclear erythroid 2-related factor2 (nuclear factor erythroid-derived 2-like 2; Nrf2) transcriptionalpathway. In one aspect, the dose comprises an oral controlled releasecomposition comprising: about 10% to about 64% by weight of one or morefumarate esters (FAE; PSD d90≤100 μm); about 18% to about 70% by weightof a mixture of mono- and di-glycerides; about 3% by weight ofpolyvinylpyrrolidone; about 10% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid. In another aspect,the dose comprises one or more FAEs in an amount of about 80 mg to about480 mg. In another aspect, the dose comprises one or more FAEs in anamount of about 80 mg to about 120 mg. In another aspect, the dosecomprises one or more FAEs in an amount of about 180 mg to about 240 mg.In another aspect, a daily total dose comprises one or more FAEs in anamount of about 360 mg to about 480 mg. In another aspect, the fumarateester comprises MMF, DMF, or a combination thereof. In another aspect,the fumarate ester comprises DMF.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 10% to about 64% by weight of one or morefumarate esters (FAE; PSD d90≤100 μm); about 18% to about 70% by weightof a mixture of mono- and di-glycerides; about 1% to about 10% by weightpolyvinylpyrrolidone; about 2% to about 10% by weight polyoxyl 40hydrogenated castor oil, and about 1% to about 5% by weight lactic acid.In one aspect, the soft capsule shell is an enteric soft capsulecomprising about 30% by weight of gelatin; about 10% by weight ofmethylacrylic acid copolymer; about 18% by weight of glycerol; about 1%by weight of triethyl citrate; about 1.5% by weight of ammonia; andabout 37% by weight of water.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 10% to about 64% by weight of one or morefumarate esters (FAE; PSD d90≤100 μm); about 18% to about 70% by weightof a mixture of mono- and di-glycerides; about 1% to about 10% by weightpolyvinylpyrrolidone; about 2% to about 10% by weight polyoxyl 40hydrogenated castor oil, and about 1% to about 5% by weight lactic acid.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 28% by weight of FAE; about 53% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid. In one aspect, thesoft capsule shell is an enteric soft capsule shell comprising about 30%by weight of gelatin; about 10% by weight of methylacrylic acidcopolymer; about 18% by weight of glycerol; about 1% by weight oftriethyl citrate; about 1.5% by weight of ammonia; and about 37% byweight of water.

Another embodiment described herein is method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 28% by weight of FAE; about 53% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 28% by weight of DMF; about 53% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 75 mg, about 80 mg, about 85 mg, about 90mg, about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg,about 115 mg, about 120 mg, about 180 mg, about 200 mg, about 210 mg,about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg,about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, orabout 480 mg of FAE; about 53% by weight of a mixture of mono- anddi-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% byweight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight oflactic acid.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 75 mg, about 80 mg, about 85 mg, about 90mg, about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg,about 115 mg, about 120 mg, about 180 mg, about 200 mg, about 210 mg,about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg,about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, orabout 480 mg of DMF; about 53% by weight of a mixture of mono- anddi-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% byweight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight oflactic acid.

Another embodiment described herein is an oral controlled releasepharmaceutical composition dosage form comprising a daily total amountof FAE of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.

Another embodiment described herein is an oral controlled releasepharmaceutical composition dosage form comprising a daily total amountof DMF of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.

Another embodiment described herein is an oral pharmaceuticalcomposition providing a daily total amount of DMF of about 180 mg, about200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg, about240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg, about440 mg, about 460 mg, or about 480 mg DMF; about 53% by weight of amixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of a pharmaceutical compositionproviding a daily total amount of FAE of about 180 mg, about 200 mg,about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg,about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg,about 460 mg, or about 480 mg.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of a pharmaceutical compositionproviding a daily total amount of DMF of about 180 mg, about 200 mg,about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg,about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg,about 460 mg, or about 480 mg.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a controlled release enteric soft capsule shelland matrix comprising: about 10% to about 64% of one or more fumarateesters (FAE; PSD<100 μm); about 18% to about 70% by weight of a mixtureof mono- and di-glycerides; at least about 3% by weight ofpolyvinylpyrrolidone; at least about 10% by weight of polyoxyl 40hydrogenated castor oil, and at least about 5% by weight of lactic acid.In one aspect, the composition comprises one or more FAEs in an amountof about 13% to about 16% by weight; about 27% to about 32% by weight;or about 53% to about 64% by weight. In another aspect, the compositioncomprises mono- and di-glycerides in an amount of about 66% to about 69%by weight; about 50% to about 55% by weight; or about 18% to about 29%by weight. In another aspect, the composition comprises one or more FAEsin an amount of about 80 mg to about 480 mg FAE. In another aspect, thecomposition comprises one or more FAEs in an amount of about 80 mg toabout 100 mg FAE; about 90 mg to about 110 mg FAE, about 100 mg to about120 mg FAE; about 180 mg to about 220 mg FAE; about 200 mg to about 240mg FAE; or about 400 to about 480 mg FAE. In another aspect, thecomposition comprises one or more FAEs in an amount of about 90 mg toabout 110 mg FAE. In another aspect, the composition comprises one ormore FAEs in an amount of about 100 mg to about 120 mg FAE. In anotheraspect, the composition comprises one or more FAEs in an amount of about200 mg to about 220 mg FAE. In another aspect, the composition comprisesone or more FAEs in an amount of about 210 mg to about 220 mg FAE. Inanother aspect, the composition comprises one or more FAEs in an amountof about 215 mg FAE. In another aspect, the composition comprises one ormore FAEs in an amount of about 1.5 to about 1.7 mmol FAE. In anotheraspect, the matrix comprises DMF, MMF, or a combination thereof. Inanother aspect, the matrix comprises DMF.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of one or more fumarate esters in anamount of about 180 mg to about 220 mg FAE, wherein the one or moredoses comprise a controlled release pharmaceutical composition thatreleases the contents at a physiological pH of about pH 6.8.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of one or more fumarate esters in anamount of about 180 mg to about 220 mg FAE, wherein the FAE comprises aprodrug of methyl hydrogen fumarate or methyl hydrogen fumarate.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of one or more fumarate esters whereinmethyl hydrogen fumarate activates a nuclear erythroid 2-related factor2 (nuclear factor erythroid-derived 2-like 2; Nrf2) transcriptionalpathway. In one aspect, the one or more doses of fumarate esterscomprise an oral controlled release composition comprising: about 10% toabout 64% by weight of one or more fumarate esters (FAE; PSD<100 μm);about 18% to about 70% by weight of a mixture of mono- anddi-glycerides; at least about 3% by weight polyvinylpyrrolidone; atleast about 10% by weight polyoxyl 40 hydrogenated castor oil, and atleast about 5% by weight lactic acid. In another aspect, the dosecomprises one or more FAEs in an amount of about 80 mg to about 480 mg.In another aspect, the dose comprises one or more FAEs in an amount ofabout 80 mg to about 120 mg. In another aspect, the dose comprises oneor more FAEs in an amount of about 180 mg to about 240 mg. In anotheraspect, a daily total dose comprises one or more FAEs in an amount ofabout 360 mg to about 480 mg. In another aspect, the FAE comprises MMF,DMF, or a combination thereof. In another aspect, the FAE comprises DMF.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule and a matrix, thematrix comprising about 10% to about 64% by weight of one or morefumarate esters (FAE; PSD d90≤100 μm); about 18% to about 70% by weightof a mixture of mono- and di-glycerides; about 1% to about 10% by weightpolyvinylpyrrolidone; about 2% to about 10% by weight polyoxyl 40hydrogenated castor oil, and about 1% to about 5% by weight lactic acid.In one embodiment, the FAE is dimethyl fumarate. In one embodiment, thesoft capsule is an enteric soft capsule shell comprising about 30% byweight of gelatin; about 10% by weight of methylacrylic acid copolymer;about 18% by weight of glycerol; about 1% by weight of triethyl citrate;about 1.5% by weight of ammonia; and about 37% by weight of water.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 10% to about 64% by weight of one or morefumarate esters (FAE; PSD d90≤100 μm); about 18% to about 70% by weightof a mixture of mono- and di-glycerides; about 1% to about 10% by weightpolyvinylpyrrolidone; about 2% to about 10% by weight polyoxyl 40hydrogenated castor oil, and about 1% to about 5% by weight lactic acid.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 28% by weight of fumarate esters; about 53%by weight of a mixture of mono- and di-glycerides; about 10% by weightof polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid. In one embodiment,the fumarate ester is dimethyl fumarate. In one embodiment, the softcapsule is an enteric soft capsule comprising about 30% by weight ofgelatin; about 10% by weight of methylacrylic acid copolymer; about 18%by weight of glycerol; about 1% by weight of triethyl citrate; about1.5% by weight of ammonia; and about 37% by weight of water.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 28% by weight of fumarate esters; about 53%by weight of a mixture of mono- and di-glycerides; about 10% by weightof polyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of an oral controlled releasepharmaceutical composition comprising a soft capsule shell and a matrix,the matrix comprising about 28% by weight of DMF; about 53% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule and a matrix, thematrix comprising about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg,about 115 mg, about 120 mg, about 180 mg, about 200 mg, about 210 mg,about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg,about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, orabout 480 mg of FAE and about 53% by weight of a mixture of mono- anddi-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% byweight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight oflactic acid. In one embodiment, the soft capsule is an enteric softcapsule comprising about 30% by weight of gelatin; about 10% by weightof methylacrylic acid copolymer; about 18% by weight of glycerol; about1% by weight of triethyl citrate; about 1.5% by weight of ammonia; andabout 37% by weight of water.

Another embodiment described herein is an oral controlled releasepharmaceutical composition comprising a soft capsule and a matrix, thematrix comprising about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 105 mg, about 108 mg, about 110 mg,about 115 mg, about 120 mg, about 180 mg, about 200 mg, about 210 mg,about 216 mg, about 220 mg, about 230 mg, about 240 mg, about 360 mg,about 400 mg, about 420 mg, about 432 mg, about 440 mg, about 460 mg, orabout 480 mg of DMF and about 53% by weight of a mixture of mono- anddi-glycerides; about 10% by weight of polyvinylpyrrolidone; about 3% byweight of polyoxyl 40 hydrogenated castor oil, and about 5% by weight oflactic acid. In one embodiment, the soft capsule is an enteric softcapsule comprising about 30% by weight of gelatin; about 10% by weightof methylacrylic acid copolymer; about 18% by weight of glycerol; about1% by weight of triethyl citrate; about 1.5% by weight of ammonia; andabout 37% by weight of water.

Another embodiment described herein is an oral controlled releasepharmaceutical composition dosage forms comprising a daily total amountof FAE of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.

Another embodiment described herein is an oral controlled releasepharmaceutical composition dosage form comprising a daily total amountof DMF of about 180 mg, about 200 mg, about 210 mg, about 216 mg, about220 mg, about 230 mg, about 240 mg, about 360 mg, about 400 mg, about420 mg, about 432 mg, about 440 mg, about 460 mg, or about 480 mg.

Another embodiment described herein is an oral pharmaceuticalcompositions providing a daily total amount of FAE of about 180 mg,about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg,about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg,about 440 mg, about 460 mg, or about 480 mg FAE; about 53% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is an oral pharmaceuticalcompositions providing a daily total amount of DMF of about 180 mg,about 200 mg, about 210 mg, about 216 mg, about 220 mg, about 230 mg,about 240 mg, about 360 mg, about 400 mg, about 420 mg, about 432 mg,about 440 mg, about 460 mg, or about 480 mg DMF; about 53% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil, and about 5% by weight of lactic acid.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of a pharmaceutical compositionproviding a daily total amount of FAE of about 180 mg, about 200 mg,about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg,about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg,about 460 mg, or about 480 mg. In one embodiment, the pharmaceuticalcomposition comprises about 28% by weight of FAE; about 53% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil; and about 5% by weight of lactic acid.

Another embodiment described herein is a method of treating multiplesclerosis in a subject in need thereof comprising orally administeringto the subject one or more doses of a pharmaceutical compositionproviding a daily total amount of DMF of about 180 mg, about 200 mg,about 210 mg, about 216 mg, about 220 mg, about 230 mg, about 240 mg,about 360 mg, about 400 mg, about 420 mg, about 432 mg, about 440 mg,about 460 mg, or about 480 mg. In one embodiment, the pharmaceuticalcomposition comprises about 28% by weight of DMF; about 53% by weight ofa mixture of mono- and di-glycerides; about 10% by weight ofpolyvinylpyrrolidone; about 3% by weight of polyoxyl 40 hydrogenatedcastor oil; and about 5% by weight of lactic acid.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating multiple sclerosis in a subject in need thereofcomprising one or more fumarate esters comprising DMF, MMF, or acombination thereof.

Another embodiment described herein is an oral pharmaceuticalcomposition for treating multiple sclerosis in a subject in need thereofcomprising one or more fumarate esters comprising DMF.

Another embodiment described herein is any of the foregoing compositionsor methods, wherein the fumarate ester comprises a therapeuticallyeffective amount of DMF, MMF, or a combination thereof.

Another embodiment described herein is any of the foregoing compositionsor methods, wherein the fumarate ester comprises a therapeuticallyeffective amount of DMF.

BRIEF DESCRIPTION OF THE DRAWINGS

Further advantageous features of the present disclosure will become moreapparent with the following detailed description when taken withreference to the accompanying drawings, each according to an aspect ofthe present disclosure:

FIG. 1. Scheme for manufacturing enteric soft capsules comprising a DMFmatrix.

FIG. 2. Dissolution of enteric soft capsules comprising two DMFformulations.

FIG. 3. DMF enteric soft capsule stability.

FIG. 4. DMF release in enteric soft capsules.

FIG. 5. Surfactant affects DMF release rate.

FIG. 6. Polyvinylpyrrolidone concentration affects DMF release rate.

FIG. 7. DMF enteric soft capsules are amenable to controlled or extendedrelease.

FIG. 8. DMF particle size affects release rate.

FIG. 9. Two-stage dissolution of application batches.

FIG. 10. Two-stage dissolution of GMP batch compared to applicationbatches.

FIG. 11. Effects of Povidone K30 and PEG 600 on DMF release rate.

FIG. 12. Two-stage dissolution of 120 mg DMF enteric soft capsule.

FIG. 13. DMF enteric soft capsule stability at T₀ and after 3- and6-month conditions.

FIG. 14. Two-stage dissolution of BLS-11 (˜215 mg) enteric soft capsule.

FIG. 15. Mean plasma concentration of MMF over time following doseadministration.

DETAILED DESCRIPTION

Described herein are pharmaceutical compositions of fumarate esters suchas dimethyl fumarate, monomethyl fumarate, other pharmacologicallyactive fumarate esters, or combinations thereof.

The pharmaceutical compositions described herein provide matrix fills offumarate esters, di-alkyl fumarates, mono-alkyl fumarates, such asdimethyl fumarate, monomethyl fumarate, or combinations thereof, andmethods for preparation thereof. Also described herein are compositionsand methods for manufacturing controlled, delayed, or extended releasefumarate esters, dimethyl fumarate, monomethyl fumarate, or combinationsthereof as soft capsule dosage forms. In one embodiment describedherein, the fumarate ester pharmaceutical composition is encapsulatedwithin an enteric soft capsule shell. In another embodiment, thefumarate ester is in the form of solid microparticles of defined sizewithin a matrix comprising a lipid or lipophilic vehicle. In someaspects, described herein, the lipid or lipophilic vehicle may comprisean amount of one or more hydrophilic polymers, but as described herein,is considered a lipid or lipophilic vehicle.

As used herein, the terms “fumarate ester” or “FAE” refers to anypharmacologically active mono- or di-alkyl fumarate ester, such asmonomethyl fumarate, dimethyl fumarate, or other fumarate esters, acids,salts, or derivatives thereof, and combinations or mixtures of any ofthe foregoing.

The terms “active ingredient” or “active pharmaceutical ingredient” asused herein refer to a pharmaceutical agent, active ingredient,compound, or substance, compositions, or mixtures thereof, that providea pharmacological, often beneficial, effect.

The terms “dosage” or “dose” as used herein denote any form of theactive ingredient formulation that contains an amount sufficient toproduce a therapeutic effect with a single administration. The dosageform used herein is for oral administration. The preferred oral dosageforms are soft capsules, or preferably, enteric soft capsules.

The terms “soft capsule” or “enteric soft capsule” as used herein referto a soft capsule shell encapsulating a liquid or semisolid “matrix” or“fill” comprising vehicles, pharmaceutically acceptable excipients, andone or more active pharmaceutical ingredients.

The terms “active pharmaceutical ingredient load” or “drug load” as usedherein refers to the quantity (mass) of the active pharmaceuticalingredient comprised in a single soft capsule fill.

The terms “formulation” or “composition” as used herein refers to thedrug in combination with pharmaceutically acceptable excipients. Thisterm includes orally administrable formulations as well as formulationsadministrable by other means.

The term “titration” as used herein refers to the incremental increasein drug dosage to a level that provides the optimal therapeutic effect.

The term “controlled release” as used herein encompasses the terms“immediate release,” “modified release,” “sustained release,” “extendedrelease,” and “delayed release.”

The terms “extended release” or “sustained release” as used hereinrefers to a composition that releases an active ingredient according toa desired profile over an extended period under physiological conditionsor in an in vitro test. By “extended period” it is meant a continuousperiod of time of at least about 1 hour; about 2 hours; about 4 hours;about 6 hours; about 8 hours; about 10 hours; about 12 hours; about 14hours; about 16 hours; about 18 hours; about 20 hours about 24 hours; oreven longer; specifically, over a period of about 18 hours underphysiological conditions or in an in vitro assay.

The term “modified release” as used herein refers to a composition thatreleases an active ingredient at a slower rate than does an immediaterelease formulation under physiological conditions or in an in vitrotest.

The term “delayed” release” as used herein refers to a composition thatreleases an active ingredient after a period of time, for exampleminutes or hours, such that the active ingredient is not releasedinitially. A delayed release composition may provide, for example, therelease of a drug or active ingredient from a dosage form, after acertain period, under physiological conditions or in an in vitro test.

The term mean “particle size distribution” (PSD) as used herein refersto the mean particle size from a statistical distribution of a range ofparticle sizes as described herein. The distribution may be a Gaussian,normal distribution, or a non-normal distribution.

The terms “d90,” “d50,” and “d10” refer to the percentage (90%, 50%, or10%, respectively) of particle sizes that are less than a specifiedsize, range, or distribution. For example, d90≤90 μm as specified meansthat 90% of the particle sizes within a distribution of particles areless than or equal to 90 μm.

The term “C_(max)” as used herein refers to the maximum observed blood(plasma, serum, or whole blood) concentration or the maximum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(min)” as used herein refers to the minimum observed blood(plasma, serum, or whole blood) concentration or the minimum bloodconcentration calculated or estimated from a concentration to timecurve, and is expressed in units of mg/L or ng/mL, as applicable.

The term “C_(avg)” as used herein refers to the blood (plasma, serum, orwhole blood) concentration of the drug within the dosing interval, iscalculated as AUC/dosing interval, and is expressed in units of mg/L orng/mL, as applicable.

The term “T_(max)” as used herein refers to the time afteradministration at which C_(max) occurs, and is expressed in units ofhours (h) or minutes (min), as applicable.

The term “AUC_(0→τ)” as used herein refers to area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime zero to time tau (τ) over a dosing interval at steady state, wheretau is the length of the dosing interval, and is expressed in units ofh·mg/L or h·ng/mL, as applicable. For example, the term AUC_(0→12) asused herein refers to the area under the concentration versus time curvefrom 0 to 12 hours.

The term “AUC_(0→∞)” as used herein refers to the area under the blood(plasma, serum, or whole blood) concentration versus time curve fromtime 0 hours to infinity, and is expressed in units of h·mg/L orh·ng/mL, as applicable.

The term “AUC_(overall)” as used herein refers to the combined areaunder the blood (plasma, serum, or whole blood) concentration versustime curve, and is expressed in units of h·mg/L (or h·ng/mL) for atleast one or more doses of the pharmaceutical compositions describedherein. In one aspect, the “AUC_(overall)” refers to the combined areaunder the blood concentration versus time curve for at least two dosesof the pharmaceutical compositions described herein.

The term “treating” refers to administering a therapy in an amount,manner, or mode effective (e.g., a therapeutic effect) to improve acondition, symptom, disorder, or parameter associated with a disorder,or a likelihood thereof.

The term “prophylaxis” refers to preventing or reducing the progressionof a disorder, either to a statistically significant degree or to adegree detectable to one skilled in the art.

The term “substantially” as used herein means to a great or significantextent, but not completely.

As used herein, all percentages (%) refer to weight percent unless notedotherwise.

The term “about” as used herein refers to any values, including bothintegers and fractional components that are within a variation of up to±10% of the value modified by the term “about.”

As used herein, “a” or “an” means one or more unless otherwisespecified.

Terms such as “include,” “including,” “contain,” “containing,” “having,”and the like mean “comprising.”

The term “or” can be conjunctive or disjunctive.

One embodiment described herein, is a controlled release pharmaceuticalcomposition comprising an enteric soft capsule shell encapsulating amatrix fill comprising one or more fumarate esters.

In another embodiment, the enteric soft capsule provides controlledrelease properties.

In another embodiment, the matrix fill provides controlled releaseproperties. Such controlled release matrix fills are described inInternational Patent Application Publication No. WO 2005/009409; U.S.Patent Application Publication No. US 2006/0115527; U.S. Pat. Nos.8,293,270; and 8,333,989, each of which is incorporated by referenceherein for such teachings. In one aspect, the matrix is configured toprovide controlled release, extended release, sustained release, delayedrelease, or combinations thereof.

In another embodiment, the matrix comprises a lipid or lipophilicvehicle that provides a suspension of fumarate ester microparticleshaving defined sizes. In one aspect, an enteric soft capsule comprisinga suspension of fumarate ester microparticles provides controlledrelease delivery of the fumarate ester.

The fumarate ester particles described herein (e.g., dimethyl fumarateor monomethyl fumarate) may be generated by any particle size reductionor particle growth methodology known to one having ordinary skill theart. Exemplary and non-limiting methods may comprise a “top-down”reduction in particle size including mechanical micronizationtechniques, wherein a larger particle is crushed, bashed, or ground intoa smaller particle through techniques, such as jet milling, ballmilling, or high pressure homogenization; or particle engineeringtechniques such as cryogenic spraying or crystal engineering. Inaddition, “bottom-up” processing may be used to build a suitable size ofparticles as described herein using dual solvent/anti-solvent rapidprecipitation techniques. See, Handbook of Pharmaceutical GranulationTechnology, CRC Press, 3rd Edition, 2010, which is incorporated byreference herein for teachings related to generating pharmaceuticalparticles. In one aspect described herein, fumarate ester particles of aspecified size distribution are produce using a milling technique.

In another embodiment, the pharmaceutical composition comprises matrixfills for fumarate esters, such as dimethyl fumarate, monomethylfumarate, or derivatives thereof, based on lipids or lipophilicvehicles. The described matrices have a hydrophobic (lipophilic) surfacein contact with the hydrophilic soft enteric capsule shell to minimizeany potential shell-fill interactions, such as when enteric softcapsules are filled with hydrophilic vehicles.

Described herein are methods for manufacturing matrix fills comprisingfumarate esters, such as dimethyl fumarate, monomethyl fumarate, orderivatives thereof, in a controlled release enteric soft capsule in theform of a suspension, where part or all of the fumarate ester issuspended within the matrix. Also provided are compositions andformulations where the fumarate ester is incorporated into a one-phaseor two-phase matrix.

Also described herein are methods for manufacturing matrix fillscomprising fumarate esters or derivatives thereof, in a delayed releaseenteric soft capsule in the form of a suspension, where part or all ofthe fumarate ester is suspended within the matrix.

Described herein are methods for manufacturing matrix fills comprisingfumarate esters or derivatives thereof, in an extended release entericsoft capsule in the form of a suspension, where part or all of thefumarate ester is suspended within the matrix.

Another embodiment described herein is a controlled, delayed, orextended release enteric soft capsule having a shell and a matrix fill,wherein the matrix fill includes fumarate esters such as dimethylfumarate, monomethyl fumarate, or derivatives thereof, suspended assolid particles in a lipid or lipophilic vehicle. In another embodiment,the lipid or lipophilic vehicle comprises a vegetable oil, hydrogenatedvegetable oil, fatty acid, wax, fatty acid ester, or a combinationthereof.

Exemplary matrix lipid or lipophilic vehicles comprise mineral oil;light mineral oil; natural oils (e.g., vegetable, corn, canola,sunflower, soybean, olive, coconut, cocoa, peanut, almond, cottonseed,persic, sesame, squalane, castor, cod liver) hydrogenated vegetable oil;partially hydrogenated oils; beeswax; polyethoxylated beeswax; paraffin;normal waxes; medium chain medium chain monoglycerides, diglycerides andtriglycerides; higher aliphatic alcohols; higher aliphatic acids; longchain fatty acids; saturated or unsaturated fatty acids; hydrogenatedfatty acids; fatty acid glycerides; polyoxyethylated oleic glycerides;monoglycerides and diglycerides; mono-, bi- or tri-substitutedglycerides; glycerol mono-oleate esters; glycerol mono-caprate; glycerylmonocaprylate; propylene glycol dicaprylate; propylene glycolmonolaurate; glyceryl palmitostearate; glyceryl behenate;diethyleneglycol palmitostearate; polyethyleneglycol stearate;polyoxyethyleneglycol palmitostearate; glyceryl mono palmitostearate;cetyl palmitate; polyethyleneglycol palmitostearate;dimethylpolysiloxane; mono- or di-glyceryl behenate; fatty alcoholsassociated with polyethoxylate fatty alcohols; cetyl alcohol; octyldodecanol; myristyl alcohol; isopropyl myristate, isopropyl palmitate,stearic acid, or stearyl alcohol, inter alia, or combinations thereof.

In one embodiment, the matrix comprises a solvent or solubilityenhancing agent. Exemplary solvents or solubility enhancing agentsuseful for the matrix fills described herein include Capmul® MCM,Captex® 355, Cremophor® RH 40, Croscarmellose, Crospovidone,Crospovidone CL, Crospovidone CL-F, Crospovidone CL-M, Imwitor® 742,Kollidon® CL, Kollidon® CL-F, Kollidon® CL-M, Labrafac™ Lipophile WL1349, Labrafil® M2125CS, Labrasol®, Lutrol® F 68, Maisine™ 35-1,mannitol, Miglyol® 812, Pearlitol® Flash, Peceol®, polyethylene glycol400, polyethylene glycol 600, polyethylene glycol 3350, Plurol® OleiqueCC 497, Povidone K 17, Povidone K 30, propylene glycol, or combinationsthereof.

In one embodiment, the matrix comprises solid particles of fumarateester suspended in a lipid or lipophilic vehicle of vegetable oil,hydrogenated vegetable oil, fatty acid, fatty acid ester, or acombination thereof. The matrix can also comprise solvents andsuspension agents such as polyethylene glycols of molecular weightranging from about 200 to about 8000 (MN, number average molecularweight), polyvinylpyrrolidone, or combinations thereof.

In another embodiment, the matrix fill comprises a release regulatorsuch as a fatty acid salt, fatty acid ester, or fatty acidpolyoxyethylene derivative. The release regulator can also be asurfactant having a hydrophilic/lipophilic balance (HLB) value betweenabout 2 and about 40. The HLB characteristic of surfactants can bedetermined in accordance with “Physical Pharmacy: Physical ChemicalPrinciples in the Pharmaceutical Sciences,” Fourth Edition, pp. 371-373,A. Martin, Ed., Lippincott Williams & Wilkins, Philadelphia (1993),which is incorporated by reference herein for such teachings.

In another embodiment, the matrix comprises emulsifying or solubilizingagents such as acacia, cholesterol, diethanolamine, glycerylmonostearate, lanolin alcohols, lecithin, mono- and di-glycerides,monoethanolamines, oleic acids, oleyl alcohols, poloxamer,polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl 40hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 80, propylene glycol diacetate, propyleneglycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, stearic acid, trolamine, emulsifying wax, or combinationsthereof.

In another embodiment, the matrix comprises a neutralizing agent.Without being bound to any theory, the neutralizing agent stabilizes thefumarate ester in the matrix fill by preventing hydrolysis. In addition,without being bound by any theory, the neutralizing agent stabilizes theenteric soft capsule shell by forming salts with the methylacrylatemoieties from the capsule shell. In one aspect, the neutralizing agentcomprises an organic acid, ester, or salt. In another aspect, theneutralizing agent comprises at least one of lactate, fumarate,caprylate, caprate, oleate, maleate, succinate, tartrate, citrate,glutamate, gluconate, esters or salts thereof, or combinations thereof.In one aspect, the neutralizing agent is lactic acid.

In another embodiment, the matrix includes a hydrophilic internal phaseand a lipid or lipophilic external phase. The hydrophilic internal phasecan comprise polypropylene glycol or polyethylene glycol of molecularweight ranging from about 200 to about 8000 (MN, number averagemolecular weight). In another embodiment, the internal phase compriseshydroalcoholic solutions of cellulose derivatives, polyacrylates,polyvinyl polymers, or combinations thereof. In one embodiment, theinternal phase comprises polymers such as methylcellulose,hydroxypropylmethylcellulose, polymethylmethacrylate, orpolyvinylpyrrolidone (PVP). In one embodiment, the internal phase of thematrix state is “fluid” or “structured.” A “fluid” internal phase, asused herein, means a completely flowable liquid whose globules canaggregate to make a larger globule. A “structured” internal phase, asused herein, means a solid, semisolid, or a gel whose shape isrelatively stable and does not usually aggregate to form a largeglobule. A structured internal phase can provide controlled drug releaseand stabilize the physical state of the matrix. Without being bound toany theory, the structured nature of the matrix impedes solvation ordiffusion of the fumarate ester out of the matrix. In anotherembodiment, the external phase comprises a vegetable oil, hydrogenatedvegetable oil, fatty acid, fatty acid ester, wax, or a combinationthereof. In another embodiment, fumarate ester is dispersed in theinternal phase as a suspension form.

In another embodiment, the matrix fill is an emulsion type, where thefumarate ester is distributed in one or both of the external(lipophilic) and internal (hydrophilic) phases. The external phase ofthe emulsion matrix fill comprises lipid or lipophilic vehicles similarto those described herein. The fumarate ester can be dispersed in theinternal phase as a solution or as a suspension. For example, oneportion of the fumarate ester in the form of a powder is incorporated inthe internal phase, while another portion is dispersed in the externalphase as solid particles. An emulsion-type matrix may comprise asurfactant or combination of surfactants having HLB values ranging fromabout 2 to about 40, including all integers within the specified range.In one aspect, the HLB range comprises from about 8 to about 20,including all integers within the specified range.

In one embodiment, the pharmaceutical composition described hereincomprises an enteric soft capsule comprising a matrix comprising a lipidor lipophilic vehicle that provides a suspension of a fumarate ester. Inone embodiment described herein, the fumarate ester is a mono- ordi-alkyl fumarate of Formula I:

wherein R₁ and R₂, which may be the same or different, independentlyrepresent hydrogen or a linear, branched, or cyclic, saturated orunsaturated C₁₋₂₀ alkyl radical, which may be optionally substitutedwith halogen (Cl, F, I, Br), hydroxy, C₁₋₄ alkoxy, nitro, or cyano forpreparing a pharmaceutical composition as described herein.

The C₁₋₂₀ alkyl radicals, C₁₋₈ alkyl radicals, and C₄₋₅ alkyl radicalsare, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethyl hexyl, hexyl,cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2or 3-hydroxy propyl, 2-methoxy ethyl, methoxy methyl or 2- or 3-methoxypropyl. In one aspect, at least one of R₁ or R₂ is a C₁₋₅ alkyl,especially methyl or ethyl. In another aspect, R₁ and R₂ are the same ordifferent C₁₋₅ alkyl radicals such as methyl, ethyl, n-propyl, ort-butyl. In one aspect, R₁ and R₂ are the same or different C₁₋₅ alkylradicals such as methyl and ethyl. In one aspect, R₁ and R₂ areidentical and are methyl or ethyl. In one aspect, the fumarate ester ismonomethyl fumarate, dimethyl fumarate, methyl ethyl fumarate, ordiethyl fumarate. In one aspect, the fumarate ester is monomethylfumarate, dimethyl fumarate, or a combination thereof. In one aspect,the fumarate ester is monomethyl fumarate. In another aspect, thefumarate ester is dimethyl fumarate.

In one embodiment, the fumarate ester is:

In one embodiment, the fumarate ester is:

In one embodiment, the pharmaceutical compositions described hereincomprise pharmaceutically acceptable salts of the active ingredient. Theterm “pharmaceutically acceptable salts” of an active ingredientincludes alkali metal salts such as, sodium or potassium salts, alkalineearth metal salts such as, for example, calcium and magnesium salts, andsalts with organic or inorganic acid such as, for example, hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,citric acid, formic acid, maleic acid, succinic acid, tartaric acid,methanesulphonic acid, toluenesulphonic acid, inter alia. In anotherembodiment, the active ingredient may also be in the form ofpharmaceutically acceptable uncharged or charged molecules, molecularcomplexes, solvates, or anhydrates thereof, and, if relevant, singleisomers, enantiomers, racemic mixtures, or mixtures thereof. In anotherembodiment, the active pharmaceutical ingredient may be in any of itscrystalline, polymorphous, semi-crystalline, amorphous or polyamorphousforms, or mixtures thereof.

The fumarate esters described herein can be prepared by processes knownin the art. See, e.g., EP 0 312 697 and U.S. Patent ApplicationPublication Nos. US 2013/0295169; US 2014/0179779; and US 2014/0200363,each of which is incorporated by reference herein for such teachings.

In one embodiment, the pharmaceutical composition comprises an activeingredient or drug. In one embodiment, the active ingredient or drug isa pharmacologically active fumarate ester. In one embodiment describedherein, the active ingredient is a dialkyl fumarate. In one embodimentdescribed herein, the active ingredient is a fumarate ester orcombination of fumarate esters. In one embodiment described herein, theactive ingredient is dimethyl fumarate. In another embodiment describedherein, the active ingredient is monomethyl fumarate. In anotherembodiment described herein, the active ingredient is a combination ofdimethyl fumarate and monomethyl fumarate. In another embodimentdescribed herein, the active ingredient is a combination of dimethylfumarate, monomethyl fumarate, and other pharmacologically activefumarate esters, acids, salts, or derivatives thereof. In anotherembodiment, the active ingredient or drug comprises dimethyl fumarate,monomethyl fumarate, other pharmacologically active fumarate esters,acids, or salts, derivatives thereof, or combinations thereof. Inanother embodiment, the active ingredient comprises dimethyl fumarate,monomethyl fumarate, or derivatives thereof, combined with aspirin,ibuprofen, naproxene, diclofenac, ketoprofen, celecoxib, othernon-steroidal anti-inflamatory active drugs (NSAIDs), or combinationsthereof. In one embodiment, the pharmaceutical composition comprises afumarate ester combined with aspirin.

In another embodiment, the pharmaceutical composition comprises afumarate ester combined with one or more leukotriene receptorantagonists. In another embodiment, the pharmaceutical compositioncomprises a fumarate ester combined with montelukast (Singulair®) orzafirlukast (Accolate®). In another embodiment, the pharmaceuticalcomposition comprises a fumarate ester combined with montelukast orzafirlukast and an NSAID. In another embodiment, the pharmaceuticalcomposition comprises a fumarate ester combined with montelukast orzafirlukast and aspirin.

In one embodiment, the fumarate ester-to-matrix ratio range comprisesfrom about 1:50 to about 1:1 by weight, including all ratios within thespecified range. In another embodiment, the fumarate ester-to-matrixratio range comprises from about 1:10 to about 1:1 by weight, includingall ratios within the specified range. In one aspect, the fumarateester-to-matrix ratio comprises about 1:9 to about 1:1 by weight,including all ratios within the specified range. In another aspect, thefumarate ester-to-matrix ratio range comprises from about 1:5 to about1:1 by weight, including all ratios within the specified range. Inanother aspect, the fumarate ester-to-matrix ratio is about 1:5; about1:4; about 1:3; about 1:2; about 1:1; or about 0.5:1. In other aspects,the fumarate ester-to-matrix ratio is 1:3.5; 1:3.1; 1:2.9; 1:2.3; or1:1.5.

In one embodiment, the active ingredient comprises about 1% to about 70%of the matrix, including all integers and fractions within the specifiedrange. In another embodiment, the active ingredient comprises about 70%;about 60%; about 50%; about 40%; about 30%; about 20%; about 15%; about10%; about 5%; about 2%; or about 1% of the matrix fill. In one aspect,the active ingredient comprises about 64% of the matrix. In anotherembodiment, the active ingredient comprises about 57% of the matrix. Inanother embodiment, the active ingredient comprises about 50% of thematrix. In another embodiment, the active ingredient comprises about 32%of the matrix. In another embodiment, the active ingredient comprisesabout 30% of the matrix. In another embodiment, the active ingredientcomprises about 28% of the matrix. In another embodiment, the activeingredient comprises about 25% of the matrix.

In one embodiment, the solid fumarate ester particles are milled ormicronized. In one embodiment, the fumarate ester comprises a particlesize range of about 1 μm to about 500 μm, including all integers andfractions within the specified range. In one aspect, the micronizedsolid fumarate ester particles have a particle size of about 1 μm, 2 μm,about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm,about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about85 μm, about 90 μm, about 95 μm, about 100 μm, about 105 μm, about 110μm, about 115 μm, about 120 μm, about 125 μm, about 130 μm, about 135μm, about 140 μm, about 145 μm, about 150 μm, about 155 μm, about 160μm, about 165 μm, about 170 μm, about 175 μm, about 180 μm, about 185μm, about 190 μm, about 195 μm, about 200 μm, about 205 μm, about 210μm, about 215 μm, about 220 μm, about 225 μm, about 230 μm, about 235μm, about 240 μm, about 245 μm, about 250 μm, about 255 μm, about 260μm, about 265 μm, about 270 μm, about 275 μm, about 280 μm, about 285μm, about 290 μm, about 295 μm, about 300 μm, about 305 μm, about 310μm, about 315 μm, about 320 μm, about 325 μm, about 330 μm, about 335μm, about 340 μm, about 345 μm, about 350 μm, about 355 μm, about 360μm, about 365 μm, about 370 μm, about 375 μm, about 380 μm, about 385μm, about 390 μm, about 395 μm, about 400 μm, about 405 μm, about 410μm, about 415 μm, about 420 μm, about 425 μm, about 430 μm, about 435μm, about 440 μm, about 445 μm, about 450 μm, about 455 μm, about 460μm, about 465 μm, about 470 μm, about 475 μm, about 480 μm, about 485μm, about 490 μm, about 495 μm, about 500 μm, or even larger. In anotheraspect, the solid particles of fumarate ester comprise a distribution ofparticle sizes, comprising particles of any of the foregoing particlesizes.

In another embodiment, the solid fumarate ester particles have meanparticle size distributions (PSD) ranging from about 20 μm, μm to about300 μm, including all integers and fractions within the specified range.In one aspect, the solid particles of fumarate ester comprise meanparticle size distributions of about 20 μm, about 30 μm, about 40 μm,about 50 μm, about 60 about 70 μm, about 80 μm, about 90 μm, about 100μm, about 120 μm, about 140 μm, about 160 μm, about 180 μm, about 190μm, about 200 μm, about 220 μm, about 240 μm, about 260 μm, about 280μm, or about 300 μm. In one aspect, the solid particles of fumarateester have a mean particle size distribution of about 260 μm. In oneaspect, the solid particles of fumarate ester have a mean particle sizedistribution of about 170 μm. In one aspect, the solid particles offumarate ester have a mean particle size distribution of about 140 μm.In one aspect, the solid particles of fumarate ester have a meanparticle size distribution of about 90 μm. In one aspect, the solidparticles of fumarate ester have a mean particle size distribution ofabout 80 μm. In one aspect, the solid particles of fumarate ester have amean particle size distribution of about 25 μm.

In another embodiment, the solid fumarate ester particles have aparticle size distribution with a d90 of less than or equal to about 500μm. In one aspect, the particle size distribution of solid particles offumarate ester have a d90 of ≤ to about 20 μm, about 30 μm, about 40 μm,about 50 μm, about 60 μm, about 70 μm, about 80 μm, about 90 μm, about100 μm, about 120 μm, about 140 μm, about 160 μm, about 180 μm, about190 μm, about 200 μm, about 220 μm, about 240 about 260 μm, about 280μm, about 300 μm, or about 400 μm. In one aspect, the solid particles offumarate ester have a particle size distribution with a d90 of ≤ about260 μm (d90≤260 μm). In one aspect, the solid particles of fumarateester have a particle size distribution with a d90 of ≤ about 170 μm, μm(d90≤170 μm). In one aspect, the solid particles of fumarate ester havea particle size distribution with a d90 of ≤ about 140 μm (d90≤140 μm).In one aspect, the solid particles of fumarate ester have a particlesize distribution with a d90 of ≤ about 100 μm (d90≤100 μm). In oneaspect, the solid particles of fumarate ester have a particle sizedistribution with a d90 of ≤ about 90 μm (d90≤90 μm). In one aspect, thesolid particles of fumarate ester have a particle size distribution witha d90 of ≤ about 80 μm (d90≤80 μm). In one aspect, the solid particlesof fumarate ester have a particle size distribution with a d90 of ≤about 25 μm (d90≤25 μm).

In another embodiment, the solid fumarate ester particles have a meanparticle size distribution comprising a range of particle sizes with ad10 of ≤10 μm and a d90 of ≤500 μm. In one aspect, the solid particlesof fumarate ester have a particle size distribution with a d10 of ≤ toabout 10 μm and a d90 of ≤ to about 400 μm, a d10 of ≤ to about 10 μmand a d90 of ≤ to about 300 μm, a d10 of ≤ to about 10 μm and a d90 of ≤to about 250 μm, a d10 of ≤ to about 10 μm and a d90 of ≤ to about 200μm, a d10 of ≤ to about 10 μm and a d90 of ≤ to about 150 μm, a d10 of ≤to about 10 μm and a d90 of ≤ to about 100 μm. In one aspect, the solidparticles of fumarate ester have a particle size distribution with a d10of ≤ to about 10 μm and a d90 of ≤ to about 100 μm, a d10 of ≤ to about20 μm and a d90 of ≤ to about 100 μm, a d10 of ≤ to about 30 μm and ad90 of ≤ to about 100 μm, a d10 of ≤ to about 40 μm and a d90 of ≤ toabout 100 μm, a d10 of ≤ to about 50 μm and a d90 of ≤ to about 100 μm,a d10 of ≤ to about 60 μm and a d90 of ≤ to about 100 μm, a d10 of ≤ toabout 70 μm and a d90 of ≤ to about 100 μm, a d10 of ≤ to about 80 μmand a d90 of ≤ to about 100 μm.

In another embodiment, the solid particles of fumarate ester comprisemultiple distributions of particle sizes. In one aspect, the solidparticles of fumarate ester may comprise a plurality of independentlycombined mean particle size distributions, wherein each independent meanparticle size distribution ranges from about 20 μm to about 300 μm,including all integers and fractions within the specified range. Inanother aspect, the plurality of mean particle size distributions cancomprise a mean particle size distribution of about 261 μm, a meanparticle size distribution of about 168 μm, a mean particle sizedistribution of about 148 μm, a mean particle size distribution of about90 μm, a mean particle size distribution of about 80 μm, or a meanparticle size distribution of about 26 μm. In another aspect, theplurality of mean particle size distributions can comprise combinationsof independent mean particle size distributions, wherein eachindependently combined mean particle size distribution is about 261 μm,about 168 μm, about 148 μm, about 90 μm, about 80 μm, or about 26 μm. Inanother aspect, the solid particles of fumarate ester comprise acombination of independently combined mean particle size distributionsof about 30 μm to about 260 μm in a single matrix fill. Any of theforegoing particle size distributions may be combined to provide thedesired controlled release profile.

The forgoing sizes of fumarate ester particles may be determined usingstandard techniques known to one of ordinary skill in the art. Theexemplary techniques that can be used for measuring the size of fumarateester particles may include laser diffraction analysis, light scattering(e.g., dynamic light scattering), microscopic particle image analysis,elutriation, or aerosol mass spectrometry. The sample of fumarate esterparticles may be measured as a dry sample or a wet sample. Anycommercially available instrument for measuring particle sizes may beused, including instruments from Cilas; Brookhaven InstrumentsCorporation; Malvern Instruments; Horiba Scientific; or Wyatt followingthe recommended operating procedures according to the manufacturer'sinstructions.

The measured particle sizes using the techniques described herein may beexpressed as a derived diameter with a normal distribution or non-normaldistribution with a mean, median (e.g., mass median diameter), and modeof particle diameter sizes. The particle size distribution may beexpressed as a diameter number distribution, a surface areadistribution, or a particle volume distribution. The mean of theparticle size distribution may be calculated and expressed in variousways, such as the volume mean diameter (D[4,3] or d₄₃), mean surfacearea diameter (D[3,2] or d₃₂) or the mean number particle diameter(D[1,0] or d₁₀). Because the particle size distribution values varydepending on the measurement methodology and how the distribution isexpressed, the comparison of different mean particle size distributionsmust be calculated by the same methodology in order to have an accuratecomparison. For example, a sample with a measured and calculated volumemean diameter must be compared with a second sample having a measuredand calculated volume mean diameter, ideally measured using the samemeasuring instrument under the same conditions. Thus, the specificparticle size distributions described herein are not intended to belimited to any one type of method for measuring or calculating aparticle size distribution (e.g., a diameter number distribution, asurface area distribution, or a particle volume distribution), butrather indicate particle size values and distributions thereof for eachmethod of measuring particle sizes described herein.

Another embodiment described herein is a method for manufacturing amatrix fill for a controlled release soft enteric capsule comprisingparticles of fumarate esters such as dimethyl fumarate or monomethylfumarate of defined sizes. In one aspect, the particles are of a similarsize distribution. In another aspect, the fumarate ester particlescomprise varied size distributions. In another aspect, the fumarateester particles comprise several size distributions. In another aspect,the fumarate ester particles comprise a mixture of smaller and largersize distributions. Without being bound to any theory, smaller particlesare generally solubilized and released more rapidly than largerparticles. The release rate can be adjusted to achieve a specifictherapeutic window over a defined period and produce controlled release,delayed release, or extended release compositions by combining multiplefumarate ester particle sizes or distributions.

Another embodiment described herein is a method for manufacturing apharmaceutical composition comprising fumarate ester(s) where thefumarate ester does not sublime during processing, manufacturing, afterproduction, or during storage. Soft enteric capsules comprising fumarateester in the matrix fills described herein are stable for months oryears. Without being bound to any theory, it is believed that suspendingsolid fumarate ester in a lipid or lipophilic vehicle comprising anorganic acid prevents or retards sublimation and stabilizes the fumarateester. In one aspect, the pharmaceutical compositions described hereinare stable at 25° C. and 60% relative humidity (RH) for about 1 month,about 2 months, about 3 months, about 4 months, about 5 months, about 6months, about 9 months, about 10 months, about 11 months, about 12months, or even longer. In another aspect, the pharmaceuticalcompositions described herein are stable for 1 year or longer at 25° C.and 60% RH. In another aspect, the pharmaceutical compositions describedherein are stable for 2 years or longer at 25° C. and 60% RH.

Another embodiment described herein is a method for preparing apharmaceutical matrix comprising a fumarate ester. An exemplary schemeof a manufacturing process is shown in FIG. 1. The method comprisesapplying heat to the matrix components during mixing or prior to mixingat about the melting point of the matrix fill composition; and thenmixing the fumarate ester with the lipid or lipophilic matrixingredients using mechanical or ultrasonic forces to form the matrixfill. The matrix fill is flowable such that it can be encapsulated usinga rotary die encapsulation machine. In one embodiment, the matrixcomponents are heated to a temperature in the range of from about 25° C.to about 70° C. In another embodiment, the matrix components are heatedto a temperature in the range of from about 25° C. to about 30° C.

In one embodiment, the matrix comprises a lipid or lipophilic vehicle, aneutralizing agent, excipients, and sold particles of fumarate ester. Inanother aspect, the matrix comprises polyethylene glycols,polyvinylpyrrolidones, oils, and surfactants. In one aspect, thesurfactant comprises polysorbate 80 or polyoxyl 40 hydrogenated castoroil. In another aspect, the matrix comprises dimethyl fumarate, amixture of mono- and di-glycerides, polyvinylpyrrolidone, polyoxyl 40hydrogenated castor oil, and lactic acid.

In one embodiment, the matrix comprising fumarate ester comprises thecomposition shown in Table 1 including all possible iterations of thespecified ranges that provide 100% for the total weight percentage ofthe composition.

TABLE 1 Exemplary Matrix Fill Composition Ingredient mg/capsule % weightFumarate Ester 240 32 (Mean PSD 80 μm) Capmul ® MCM 375 50 Povidone K 30 15-52.5 0.01-7   Cremophor ® RH 40 15-75   2-10 Lactic acid 7.5-37.51-5 TOTAL 750 mg 100%

In one embodiment, the matrix comprises about 32% by weight of fumarateester (PSD: 80 μm); about 50% by weight of a mixture of mono- anddi-glycerides; at least about 0.01-7% by weight of polyvinylpyrrolidone;at least about 2-10% by weight of polyoxyl 40 hydrogenated castor oil,and at least about 1-5% by weight of lactic acid, including alliterations of the specified ranges. In one aspect, the compositionprevents sublimation of the FAE during processing and manufacturing. Inone aspect, the composition reduces the onset of symptoms ofgastrointestinal side effects. In another aspect, the composition isstable for at least 6 months at 25° C. and 60% relative humidity. In oneaspect, the composition is stable for at least 24 months.

In one embodiment, the matrix comprises the composition shown in Table 2including all possible iterations of the specified ranges that provide100% for the total weight percentage.

TABLE 2 Exemplary Matrix Fill Composition Ingredient mg/capsule % weightFumarate ester 480 48-60 PSD: d90 ≤ 100 μm Capmul ® MCM 216-470  25-48.0 Cremophor ® RH 40 7.3-120  0.85-12.0 Povidone K 30 7.3-50 0.85-5.0  Lactic acid 21.7-50   2.55-5.0  TOTAL 750 mg-1000 mg 100%

In another embodiment the matrix fill comprises about 32% of fumarateester (PSD: ≤90 μm); about 25% to about 47% of a mixture of mono- anddi-glycerides; at least about 0.01-7% polyvinylpyrrolidone; at leastabout 0.85-12% polyoxyl 40 hydrogenated castor oil, and at least about1-5% lactic acid, including all iterations of the specified ranges. Inone aspect, the composition prevents sublimation of the FAE duringprocessing and manufacturing. In another aspect, the composition reducesthe onset of symptoms of any gastrointestinal side effects. In anotheraspect, the composition is stable for at least 6 months at 25° C. and60% relative humidity. In another aspect, the composition is stable forat least 24 months at 25° C. and 60% relative humidity.

In one embodiment, the fumarate ester pharmaceutical compositioncomprises a soft gelatin capsule shell comprising a matrix comprising afumarate ester.

In one embodiment, the fumarate ester pharmaceutical compositioncomprises an enteric soft capsule shell comprising a matrix comprising afumarate ester. Enteric soft capsules are described in InternationalPatent Application Publication No. WO 2004/030658; U.S. PatentApplication Publication No. US 2006/0165778; and U.S. Pat. No.8,685,445, each of which is incorporated by reference herein for suchteachings. The enteric soft capsule shell may comprise one or more filmforming polymers, one or more enteric acid-insoluble polymers, one ormore plasticizers, one or more alkali-neutralizing agents, one or moresolvents, optionally one or more colorants, and optionally one or moreflavorings or other conventionally accepted pharmaceutical excipients oradditives.

Film-forming polymers that are useful for creating enteric soft capsulesare gelatin or hydroxypropylmethylcellulose (HPMC). In one aspect of theenteric soft capsule shell described herein, the film-forming polymer isgelatin.

Examples of enteric, acid-insoluble polymers are acrylic andmethacrylate acid copolymers, cellulose acetate phthalate (CAP),cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate(HPMCP), algenic acid salts such as sodium or potassium alginate, orshellac. Poly(methacylic acid-co-methyl methacrylate) anionic copolymersbased on methacrylic acid and methyl methacrylate are particularlystable and are preferred in some embodiments. Poly(meth)acrylates(methacrylic acid copolymer), available under the trade name EUDRAGIT®(Evonik Industries AG, Essen, Germany), are provided as powder oraqueous dispersions. In another aspect, the methacrylic acid copolymercomprises EUDRAGIT® L 30 D-55; EUDRAGIT® L 100-55; EUDRAGIT® L 100;EUDRAGIT® L 12.5; EUDRAGIT® S 100; EUDRAGIT® S 12.5; EUDRAGIT® FS 30 D;EUDRAGIT® E 100; EUDRAGIT® E 12.5; EUDRAGIT® E PO; EUDRAGIT® RL 100;EUDRAGIT® RL PO; EUDRAGIT® RL 30 D; EUDRAGIT® RL 12.5; EUDRAGIT® RS 100;EUDRAGIT® RS PO; EUDRAGIT® RS 30 D; EUDRAGIT® RS 12.5; EUDRAGIT® NE 30D; EUDRAGIT® NE 40 D; EUDRAGIT® NM 30 D; other poly(meth)acrylatepolymers; or a mixture thereof. In one aspect, the enteric polymer isEUDRAGIT® L 100, a methacrylic acid copolymer, Type A. Acid-insolublepolymer specifications are detailed in the United States Pharmacopoeiaand in various monographs.

In another embodiment described herein, the enteric polymer in theenteric soft capsule shell comprises poly(methacylic acid-co-ethylacrylate) 1:1 (e.g., EUDRAGIT® L 100-55). In one embodiment describedherein, the enteric polymer comprises poly(ethyl acrylate-co-methylmethacrylate) 2:1 (e.g., EUDRAGIT® NE 40 D). In another embodimentdescribed herein, the enteric polymer comprises poly(methylacrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 (e.g.,EUDRAGIT® FS 30 D). In another embodiment described herein, the entericpolymer comprises a combination of poly(methacylic acid-co-ethylacrylate) 1:1 and poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1. In another embodiment, theenteric polymer comprises a combination of poly(methacylic acid-co-ethylacrylate) 1:1 and poly(ethyl acrylate-co-methyl methacrylate) 2:1. Inanother embodiment, the enteric polymer comprises a combination ofpoly(methacylic acid-co-ethyl acrylate) 1:1, poly(ethylacrylate-co-methyl methacrylate) 2:1, and poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1.

In another embodiment, plasticizers that are useful for creating entericsoft capsules as described herein are glycerol, sorbitol, SorbitolSpecial®, maltitol, corn syrup, propylene glycol, poly-alcohols with 3to 6 carbon atoms, polyethylene glycol, citric acid, citric acid esters,such as tri-ethyl citrate, or combinations thereof. The weight ratiobetween the film-forming polymer, the enteric acid-insoluble polymer,and plasticizer is adjusted so that the gel mass is flowable and not tooviscous, and can be made into soft capsules using rotary dieencapsulation methods.

In one embodiment, enteric soft capsule shell compositions are made bydissolving the enteric acid-insoluble polymer in an aqueous solution ofan alkali-neutralizing agent such as ammonia, sodium hydroxide,potassium hydroxide, or liquid amines such as tri-ethanol amine orethylene diamine. The amount of alkali is adjusted to give a final pHvalue of the gel mass less than or equal to about pH 9.0. In oneembodiment, the final pH does not exceed 8.5. The volatilealkali-neutralizing agent, ammonia is preferred. The film-formingpolymer can then be combined with the plasticizer and solvent and thenblended with the acid-insoluble gel to make a final homogeneous mix in aheat-controlled vessel with degassing by vacuum. The fugitive ammoniaevaporates during degassing. Using the foregoing process, the alkaliconcentrations do not require heating or neutralizing with acid in orderto neutralize the gel mass.

In another embodiment described herein, the enteric soft capsule shellis made using an aqueous dispersion of the acid-insoluble polymer byadding an alkali-neutralizing agent such as ammonium, sodium, orpotassium hydroxides, other alkalis, or a combination thereof that willcause the enteric acid-insoluble polymer to dissolve. Theplasticizer-wetted, film-forming polymer can then be mixed with thesolution of the acid-insoluble polymer. In one embodiment, entericacid-insoluble polymers in the form of salts of the bases or alkalis asdescribed herein are dissolved directly in water and mixed with theplasticizer-wetted, film-forming polymer.

In one embodiment described herein, enteric acid-insoluble polymers inthe form of salts of the bases or alkalis described herein are dissolveddirectly in water and mixed with the plasticizer-wetted, film-formingpolymer. In another embodiment described herein, an aqueous dispersionof the acid-insoluble polymer or polymers is used, which obviates theneed for the addition of the alkali-neutralizing agent described herein.

In one embodiment, the enteric soft capsule shell has the composition ofTable 3, including all possible iterations of the specified ranges thatprovide 100% for the total weight percentage, including or excluding theoptional, excipients, opacifiers, colorants, and flavorings.

TABLE 3 Enteric Soft Capsule Shell Composition Composition ComponentExemplary Component Range (%) Film-forming polymer Gelatin 20-36Enteric, acid-insoluble Methacrylic Acid Copolymer  8-20 polymerPlasticizer Glycerol, sorbitol, Triethyl 15-22 citrateAlkali-neutralizing agents NH₄OH (30%), NaOH 1-5 Solvent Water 20-40Opacifier Titanium Dioxide  1-7.5 Colorant (optional) Various 0.05-1  Flavoring (optional) Various 0.05-2   Excipients (optional) Various 1-5

In one embodiment, the enteric soft capsule shell comprises acomposition of about 30% film forming polymer; about 10% enteric,acid-insoluble polymer; about 20% plasticizer; about 1%alkali-neutralizing agent; and about 37% solvent.

In another embodiment, the weight percentage range of total polymercontent (i.e., film forming polymer and enteric acid-insoluble polymer)of the enteric soft capsule described herein is about 30% to about 45%,including all integers and fractions within the specified range. In oneaspect, the total polymer weight percentage is about 40%. In anotheraspect, the total polymer weight percentage is about 42%. In anotheraspect, the total polymer weight percentage is about 45%. In anotheraspect, the total polymer weight percentage is about 38%.

In one embodiment, the weight percentage range of total plasticizer isabout 15% to about 22%, including all integers and fractions within thespecified range. In one aspect, the total plasticizer weight percentageis about 19%. In another aspect, the total plasticizer weight percentageis about 17.7%. In another aspect, the total plasticizer weightpercentage is about 18.9%. In another aspect, the total plasticizerweight percentage is about 19.3%.

In one embodiment, the alkali-neutralizing agent is ammonia (ammoniumhydroxide; 30% w/v) that is added to comprise a weight percentage ofabout 1% to about 5% of the total enteric soft capsule composition. Inone aspect, 30% w/v ammonia is added to comprise a weight percentage ofabout 2%. In another aspect, 30% w/v ammonia is added to comprise aweight percentage of about 1.7%. In one aspect, ammonia is added toprovide a final pH of about 9 in the enteric soft capsule composition.In another aspect, ammonia is added to provide a final pH of about 8.5in the enteric soft capsule composition. In another aspect, after thecapsules are filled and dried, the ammonia concentration issubstantially reduced, owing to the fugitive nature of the volatilealkali-neutralizing agent. In another aspect, practically all of theammonia is evaporated except for ammonium ions comprising salts withother moieties in the composition.

In one embodiment, the weight ratio range of film forming polymer toenteric acid-insoluble polymer (i.e., film forming:enteric) is about25:75 (≈0.33) to about 40:60 (≈0.67) (i.e., ≈0.33-0.67), including allratios within the specified range. In one aspect, the ratio of filmforming polymer to enteric acid-insoluble polymer is about 30:70(≈0.43). In another aspect, the ratio of film forming polymer to entericacid-insoluble polymer is about 28:72 (≈0.38).

In one embodiment, the weight ratio of total plasticizer to film formingpolymer is about 20:40 to 21:30 (i.e., ≈0.5-0.7), including all ratioswithin the specified range. In one aspect, the weight ratio of totalplasticizer to film forming polymer is about 20:40 (≈0.5). In anotheraspect, the weight ratio of total plasticizer to film forming polymer isabout 21:30 (≈0.7). In another aspect, the weight ratio of totalplasticizer to film forming polymer is about 19:29 (≈0.65). In anotheraspect, the weight ratio of total plasticizer to film forming polymer isabout 19.3:29.2 (≈0.66).

In one embodiment, the weight ratio of total plasticizer to entericacid-insoluble polymer is about 1:1 to about 2:1 (≈1-2), including allratios within the specified range. In one aspect, the weight ratio oftotal plasticizer to enteric acid-insoluble polymer is about 11:10(≈1.1). In another aspect, the weight ratio of total plasticizer toenteric acid-insoluble polymer is about 14:10 (≈1.4). In another aspect,the weight ratio of total plasticizer to enteric acid-insoluble polymeris about 17:10 (≈1.7). In another aspect, the weight ratio of totalplasticizer to enteric acid-insoluble polymer is about 20:10 (≈2). Inanother aspect, the weight ratio of total plasticizer to entericacid-insoluble polymer is about 19.3:11.2 (≈1.73).

In one embodiment, the weight ratio range of total plasticizer to totalpolymer (film forming and enteric acid-insoluble polymer) is about 18:45to about 20:40 (i.e., ≈0.40-0.5), including all ratios within thespecified range. In one aspect, the weight ratio range of totalplasticizer to total polymer is about 18:45 (≈0.40). In another aspect,the weight ratio range of total plasticizer to total polymer is about19:40 (≈0.475). In another aspect, the weight ratio range of totalplasticizer to total polymer is about 20:40 (≈0.5). In another aspect,the weight ratio range of total plasticizer to total polymer is about19.3:40.4 (≈0.477).

In one embodiment, the solvent comprises about 20% to about 40% of theenteric soft capsule composition, including all integers and fractionswithin the specified range. In one embodiment, the solvent is water. Thequantity of water in the composition varies depending on the quantitiesof the other ingredients. For example, the quantity of opacifier,colorant, flavoring, or other excipients can change the percentage ofwater present in the composition. In one embodiment, the weightpercentage of water is as much as suffices to bring the total weightpercentage to 100% (i.e., quantum sufficiat; q.s.). In anotherembodiment, the water comprises about 20%, about 25%, about 30%, about35%, or about 40% of the enteric soft capsule composition. In anotherembodiment, water comprises about 35% to about 40% of the enteric softcapsule composition. In one embodiment, water comprises about 37% of thecomposition.

In one embodiment, the final moisture (water) content of the entericsoft capsule is from about 8% to about 15%, including all integers andfractions within the specified range. In another embodiment, themoisture content is about 8% to about 12%, including all integers andfractions within the specified range. In one aspect, the final moisturecontent is about 8%. In one aspect, the final moisture content is about9%. In one aspect, the final moisture content is about 10%. In oneaspect, the final moisture content is about 11%. In another aspect, thefinal moisture content is about 12%.

In one embodiment, the enteric soft capsule shell has the exemplarycomposition shown in Table 4.

TABLE 4 Exemplary Enteric Soft Capsule Shell Composition PercentComponent weight (%) Gelatin 29.2 Methacrylic Acid Copolymer (EUDRAGIT ®L 100) 11.2 Glycerol or Sorbitol 18.0 Triethyl citrate  1.3 Ammoniumhydroxide  1.7 Titanium dioxide  1.5 Water 37.1 TOTAL  100% Final pH8.5-9.0 Total polymer % weight (gelatin + enteric) 40.4% Gelatin % wt oftotal polymer (gelatin + enteric) 72.4% Enteric % wt of total polymer(gelatin + enteric) 27.6% Ratio of Enteric to Gelatin 11.2:29.2 (0.38)Total plasticizer % weight (glycerol + triethyl citrate) 19.3% Ratio oftotal plasticizer to total polymer 19.3:40.4 (0.48) Ratio totalplasticizer to gelatin 19.3:29.2 (0.66) Ratio total plasticizer toenteric 19.3:11.2 (1.73) Water content in dried enteric soft capsule:8-15%

In one embodiment, the enteric soft capsule shell comprises about 30%gelatin; about 10% poly(methyl) acrylate copolymer; about 18% glycerol;about 1% triethyl citrate; about 1.5% ammonia; about 37% water; andabout 1.5% titanium dioxide.

In another embodiment, the enteric soft capsule is described in U.S.Provisional Patent Application No. 62/015,063, which is incorporated byreference herein for such teachings.

One embodiment described herein provides an enteric acid-insolublepolymer dispersed within the film-forming polymer gel mass that providesthe total soft gel composition with enteric acid-insoluble properties,at relatively low concentrations of the enteric acid-insoluble polymer(e.g., from about 8% to about 20% of the total wet gel mass composition)and without the need of excessive amounts of alkali, thus avoidingdenaturation or degradation of the film-forming polymer that can weakenthe integrity of the enteric soft capsule shell.

Films of the enteric soft capsule shell do not dissolve or disintegratein acids, such as 0.1 N hydrochloric acid or simulated gastric fluid(ca. pH 1.2), despite the fact that the majority of the shellingredients (i.e., greater than 50%) normally dissolve in, or aremiscible with, acids. Enteric soft capsules made using the compositionsdescribed herein remain intact in hydrochloric acid or simulated gastricfluid for at least two hours. The capsules readily release the contentsupon shifting the pH of the solution to ca. 6.8, such as that ofsimulated intestinal fluid.

In another embodiment, the final enteric capsule composition providesfilms of increased strength without substantially compromising filmelasticity. Moreover, films made from the enteric soft capsulecompositions as described herein are sealed at normal temperature rangetypically used for making traditional soft gel capsules. In one aspect,enteric soft capsules are made using a rotary die apparatus as describedin U.S. Pat. Nos. 5,459,983; 5,146,730; and 6,482,516, each of which areincorporated by reference herein for such teachings.

Another embodiment described herein includes a process of manufacturingenteric soft capsules comprising the pharmaceutical composition asdescribed herein. The process includes preparing a gel mass compositioncomprising a film-forming, water-soluble polymer and an entericacid-insoluble polymer and mixing with appropriate plasticizers andsolvent; casting the gel mass into films or ribbons usingheat-controlled drums or surfaces; and manufacturing a soft capsulecomprising a matrix fill using rotary die technology. The thickness ofthe films or ribbons that form the enteric capsule shell is from about0.010 inches (≈0.254 mm) to about 0.050 inches (≈1.27 mm), including allintegers and fractions within the specified range. The shell thicknesscomprises about 0.010 inch (≈0.254 mm), about 0.015 inch (≈0.381 mm),about 0.02 in (≈0.508 mm), about 0.03 in (≈0.762 mm), about 0.04 in(≈1.02 mm), or about 0.05 in (≈1.27 mm). In one embodiment, thethickness is about 0.02 inches (≈0.508 mm) to about 0.040 inches (≈1.02mm). In one embodiment, the shell thickness is about 0.028 inches(≈0.711 mm). In another embodiment, the shell thickness is about 0.033inches (≈0.838 mm). In another embodiment, the shell thickness is about0.038 inches (≈0.965 mm).

In one embodiment described herein, the enteric soft capsule shelldescribed herein, encapsulates a matrix fill as described herein. Inanother embodiment described herein, the enteric soft capsule shell andencapsulated matrix fill comprises an outer dimension from about 2 ovalto about 30 oval including all iterations of capsule size within thespecified range (e.g., 2 oval, 3 oval, 4 oval, 5 oval, 6 oval, 7 oval, 8oval, 10 oval, 12 oval, 16 oval, 20 oval, or 30 oval). In anotherembodiment described herein, the enteric soft capsule shell andencapsulated matrix fill comprises an outer dimension from about 2 roundto about 28 round including all iterations of capsule size within thespecified range (e.g., 2 round, 3 round, 4 round, 5 round, 6 round, 7round, 8 round, 10 round, 12 round, 16 round, 20 round or 28 round). Inanother embodiment described herein, the enteric soft capsule shell andencapsulated matrix fill comprises an outer dimension from about 2oblong to about 22 oblong including all iterations of capsule sizewithin the specified range (e.g., 2 oblong, 3 oblong, 4 oblong, 5oblong, 6 oblong, 7 oblong, 8 oblong, 10 oblong, 11, oblong, 12 oblong,14 oblong, 16 oblong, 20 oblong, or 22 oblong). Dimension specificationsof soft capsules and tablets are known to those of ordinary skill in theart. See Remington's Essentials of Pharmaceutics, Pharmaceutical PressPublishing Company, London, UK, 1^(st) Edition, 2013, which isincorporated by reference herein for such teachings.

The enteric soft capsules described herein can contain a matrix fillthat is liquid, semi-solid, or solid. Capsules prepared as describedherein can contain a hydrophobic solution or suspension, such asvegetable oils or shortening, or waxes, or combinations thereof. Thematrix fill can be formulated to prevent interaction with the capsuleshell components and release the pharmaceutical composition at aspecified rate.

One embodiment described herein, is a pharmaceutical compositioncomprising a matrix fill formulation comprising any of the formulationsshown in the Tables or Examples described herein. Any of the componentsof the formulations shown in the Tables or Examples can be increased,decreased, combined, recombined, switched, or removed to provide for aformulation comprising about 100% by weight.

In one embodiment, the pharmaceutical composition described hereinprovides a dosage of fumarate ester for administration to a subject. Thedosage form can be administered, for example, to a subject, or a subjectin need thereof. In one aspect, the subject is a mammal, or a mammal inneed thereof. In one aspect, the subject is a human, or human in needthereof. In one aspect, the human or human in need thereof is a medicalpatient. In one aspect, the human subject is a child (˜0-9 years old) oran adolescent (˜10-17 years old). In one aspect, the subject is fromabout 0 to about 9 years of age. In another aspect, the human subject isfrom about 10 years to about 17 years of age. In another aspect, thehuman subject is over 17 years of age. In another aspect, the humansubject is an adult (≥18 years of age).

The dosage form can be administered, for example, lx, 2×, 3×, 4×, 5×,6×, or even more times per day. One or more dosage form can beadministered, for example, for 1, 2, 3, 4, 5, 6, 7 days, or even longer.One or more dosage forms can be administered, for example, for 1, 2, 3,4 weeks, or even longer. One or more dosage forms can be administered,for example, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, 1 year,2, years, 3 years, 4 years, 5 years, over 5 years, a decade, multipledecades, or even longer. One or more dosage forms can be administered ata regular interval until the subject or subject in need thereof, doesnot require treatment, prophylaxis, or amelioration of any disease orcondition including but not limited to, general autoimmune orneurodegenerative disorders.

In one embodiment, the pharmaceutical composition described herein isadministered in multiple dosages simultaneously. For example, two ormore identical dosages are administered at one time. In anotherembodiment, two or more different dosages are administered at one time.Such dual or different simultaneous doses can be used to provide aneffective amount of the pharmaceutical composition to a subject in needthereof.

In another embodiment, the pharmaceutical composition described hereinmay be used to treat, prevent, retard the progression of, delay theonset, ameliorate, reduce the symptoms of, or prophylaxis of generalautoimmune or neurodegenerative disorders. Neurodegenerative disorders,as used herein, include multiple sclerosis (MS), which includesrelapsing remitting multiple sclerosis (RRMS), secondary progressivemultiple sclerosis (SPMS), primary progressive multiple sclerosis(PPMS), progressive relapsing multiple sclerosis (PPvMS), amyotrophiclateral sclerosis (ALS), psoriasis, psoriatic arthritis, Alzheimer'sdisease, Parkinson's disease, or any combination thereof.

In one embodiment described herein, other conditions, disorders, ordiseases are controlled by administration of fumarate esters. Theadministration of pharmaceutical compositions comprising fumarateesters, as described herein, may be used for treating, preventing,retarding the progression of, delaying the onset, ameliorating, reducingthe symptoms of, or prophylaxis of general autoimmune orneurodegenerative disorders, including but not limited to, acutedermatitis, adrenal leukodystrophy, AGE-induced genome damage,Alexander's disease, alopecia areata (totalis and universalis), Alper'sdisease, Alzheimer's disease, amyotrophic lateral sclerosis, anginapectoris, arthritis, asthma, autoimmune diseases, balo concentricsclerosis, Behcet's syndrome, bullous pemphigoid, Canavan disease,cardiac insufficiency including left ventricular insufficiency, centralnervous system vasculitis, Charcot-Marie-Tooth disease, childhood ataxiawith central nervous system hypomyelination, chronic active (lupoid)hepatitis, chronic dermatitis, chronic idiopathic peripheral neuropathy,chronic obstructive pulmonary disease, contact dermatitis, Crohn'sdisease and cutaneous Crohn's disease, cutaneous lupus, cutaneoussarcoidosis, diabetic retinopathy, fibromyalgia, graft versus hostdisease, granuloma annulare, granulomas including annulare, Grave'sdisease, Hashimoto's thyroiditis, hepatitis C viral infection, herpessimplex viral infection, human immunodeficiency viral infection,Huntington's disease, inflammatory bowel disease, irritable boweldisorder, ischemia, juvenile-onset diabetes mellitus, Krabbe disease,lichen planus, macular degeneration, mitochondrial encephalomyopathy,monomelic amyotrophy, multiple sclerosis (MS), myocardial infarction,necrobiosis lipoidica, neurodegeneration with brain iron accumulation,neurodermatitis, neuromyelitis optica, neuropathic pain,neurosarcoidosis, NF-κB mediated diseases, optic neuritis, organtransplantation rejection, paraneoplastic syndromes, Parkinson'sdisease, Pelizaeus-Merzbacher disease, pemphigus, pernicious anemia,primary lateral sclerosis, progressive supranuclear palsy, psoriasis,psoriatic arthritis, pyoderma gangrenosum, radicular pain,radiculopathic pain, reperfusion injury, retinopathic pigmentosa,rheumatoid arthritis (RA), sarcoidosis, sarcoidosis, Schilder's disease,sciatic pain, sciatica, Sjögren's syndrome, subacute necrotizingmyelopathy, such as polyarthritis, Susac's syndrome, systemic lupuserythematosus (SLE), tumors, transverse myelitis, ulcerative colitis, orZellweger syndrome.

One embodiment described herein comprises a method for orallyadministering a dosage form that provides a total amount of fumarateester of about 20 mg to about 1000 mg (e.g., ˜20-1000 mg), including allintegers and fractions within the specified range.

In one embodiment described herein, the fumarate ester (FAE) dosage formcan comprise, but is not limited to about 50 mg FAE, about 55 mg FAE,about 60 mg FAE, about 65 mg FAE, about 70 mg FAE, about 75 mg FAE,about 80 mg FAE, about 85 mg FAE, about 90 mg FAE, about 95 mg FAE,about 100 mg FAE, about 105 mg FAE, about 110 mg FAE, about 115 mg FAE,about 120 mg FAE, about 125 mg FAE, about 130 mg FAE, about 135 mg FAE,about 140 mg FAE, about 145 mg FAE, about 150 mg FAE, about 155 mg FAE,about 160 mg FAE, about 165 mg FAE, about 170 mg FAE, about 175 mg FAE,about 180 mg FAE, about 185 mg FAE, about 190 mg FAE, about 195 mg FAE,about 200 mg FAE, about 205 mg FAE, about 210 mg FAE, about 215 mg FAE,about 220 mg FAE, about 225 mg FAE, about 230 mg FAE, about 235 mg FAE,about 240 mg FAE, about 245 mg FAE, about 250 mg FAE, about 255 mg FAE,about 260 mg FAE, about 265 mg FAE, about 270 mg FAE, about 275 mg FAE,about 280 mg FAE, about 285 mg FAE, about 290 mg FAE, about 295 mg FAE,about 300 mg FAE, about 305 mg FAE, about 310 mg FAE, about 315 mg FAE,about 320 mg FAE, about 325 mg FAE, about 330 mg FAE, about 335 mg FAE,about 340 mg FAE, about 345 mg FAE, about 350 mg FAE, about 355 mg FAE,about 360 mg FAE, about 365 mg FAE, about 370 mg FAE, about 375 mg FAE,about 380 mg FAE, about 385 mg FAE, about 390 mg FAE, about 395 mg FAE,about 400 mg FAE, about 405 mg FAE, about 410 mg FAE, about 415 mg FAE,about 420 mg FAE, about 425 mg FAE, about 430 mg FAE, about 435 mg FAE,about 440 mg FAE, about 445 mg FAE, about 450 mg FAE, about 455 mg FAE,about 460 mg FAE, about 465 mg FAE, about 470 mg FAE, about 475 mg FAE,or about 480 mg FAE. In one embodiment, the foregoing dosages comprise apartial dose, e.g., including but not limited to one dose of a twice orthrice daily regimen. In another embodiment, any of the foregoingdosages comprise a total daily dose.

In another embodiment described herein, the fumarate ester (FAE) dosageform can comprise, but is not limited to about 50 mg FAE, about 52 mgFAE, about 54 mg FAE, about 56 mg FAE, about 58 mg FAE, about 60 mg FAE,about 62 mg FAE, about 64 mg FAE, about 66 mg FAE, about 68 mg FAE,about 70 mg FAE, about 72 mg FAE, about 74 mg FAE, about 76 mg FAE,about 78 mg FAE, about 80 mg FAE, about 82 mg FAE, about 84 mg FAE,about 86 mg FAE, about 88 mg FAE, about 90 mg FAE, about 92 mg FAE,about 94 mg FAE, about 96 mg FAE, about 98 mg FAE, about 100 mg FAE,about 102 mg FAE, about 104 mg FAE, about 106 mg FAE, about 108 mg FAE,about 110 mg FAE, about 112 mg FAE, about 114 mg FAE, about 116 mg FAE,about 118 mg FAE, about 120 mg FAE, about 122 mg FAE, about 124 mg FAE,about 126 mg FAE, about 128 mg FAE, about 130 mg FAE, about 132 mg FAE,about 134 mg FAE, about 136 mg FAE, about 138 mg FAE, about 140 mg FAE,about 142 mg FAE, about 144 mg FAE, about 146 mg FAE, about 148 mg FAE,about 150 mg FAE, about 152 mg FAE, about 154 mg FAE, about 156 mg FAE,about 158 mg FAE, about 160 mg FAE, about 162 mg FAE, about 164 mg FAE,about 166 mg FAE, about 168 mg FAE, about 170 mg FAE, about 172 mg FAE,about 174 mg FAE, about 176 mg FAE, about 178 mg FAE, about 180 mg FAE,about 182 mg FAE, about 184 mg FAE, about 186 mg FAE, about 188 mg FAE,about 190 mg FAE, about 192 mg FAE, about 194 mg FAE, about 196 mg FAE,about 198 mg FAE, about 200 mg FAE, about 202 mg FAE, about 204 mg FAE,about 206 mg FAE, about 208 mg FAE, about 210 mg FAE, about 212 mg FAE,about 214 mg FAE, about 216 mg FAE, about 218 mg FAE, about 220 mg FAE,about 222 mg FAE, about 224 mg FAE, about 226 mg FAE, about 228 mg FAE,about 230 mg FAE, about 232 mg FAE, about 234 mg FAE, about 236 mg FAE,about 238 mg FAE, about 240 mg FAE, about 242 mg FAE, about 244 mg FAE,about 246 mg FAE, about 248 mg FAE, about 250 mg FAE, about 252 mg FAE,about 254 mg FAE, about 256 mg FAE, about 258 mg FAE, about 260 mg FAE,about 262 mg FAE, about 264 mg FAE, about 266 mg FAE, about 268 mg FAE,about 270 mg FAE, about 272 mg FAE, about 274 mg FAE, about 276 mg FAE,about 278 mg FAE, about 280 mg FAE, about 282 mg FAE, about 284 mg FAE,about 286 mg FAE, about 288 mg FAE, about 290 mg FAE, about 292 mg FAE,about 294 mg FAE, about 296 mg FAE, about 298 mg FAE, about 300 mg FAE,about 302 mg FAE, about 304 mg FAE, about 306 mg FAE, about 308 mg FAE,about 310 mg FAE, about 312 mg FAE, about 314 mg FAE, about 316 mg FAE,about 318 mg FAE, about 320 mg FAE, about 322 mg FAE, about 324 mg FAE,about 326 mg FAE, about 328 mg FAE, about 330 mg FAE, about 332 mg FAE,about 334 mg FAE, about 336 mg FAE, about 338 mg FAE, about 340 mg FAE,about 342 mg FAE, about 344 mg FAE, about 346 mg FAE, about 348 mg FAE,about 350 mg FAE, about 352 mg FAE, about 354 mg FAE, about 356 mg FAE,about 358 mg FAE, about 360 mg FAE, about 362 mg FAE, about 364 mg FAE,about 366 mg FAE, about 368 mg FAE, about 370 mg FAE, about 372 mg FAE,about 374 mg FAE, about 376 mg FAE, about 378 mg FAE, about 380 mg FAE,about 382 mg FAE, about 384 mg FAE, about 386 mg FAE, about 388 mg FAE,about 390 mg FAE, about 392 mg FAE, about 394 mg FAE, about 396 mg FAE,about 398 mg FAE, about 400 mg FAE, about 402 mg FAE, about 404 mg FAE,about 406 mg FAE, about 408 mg FAE, about 410 mg FAE, about 412 mg FAE,about 414 mg FAE, about 416 mg FAE, about 418 mg FAE, about 420 mg FAE,about 422 mg FAE, about 424 mg FAE, about 426 mg FAE, about 428 mg FAE,about 430 mg FAE, about 432 mg FAE, about 434 mg FAE, about 436 mg FAE,about 438 mg FAE, about 440 mg FAE, about 442 mg FAE, about 444 mg FAE,about 446 mg FAE, about 448 mg FAE, about 450 mg FAE, about 452 mg FAE,about 454 mg FAE, about 456 mg FAE, about 458 mg FAE, about 460 mg FAE,about 462 mg FAE, about 464 mg FAE, about 466 mg FAE, about 468 mg FAE,about 470 mg FAE, about 472 mg FAE, about 474 mg FAE, about 476 mg FAE,about 478 mg FAE, or about 480 mg FAE. In one embodiment, the foregoingdosages comprise a partial dose, e.g., including but not limited to onedose of a twice or thrice daily regimen. In another embodiment, any ofthe foregoing dosages comprise a total daily dose.

In one embodiment, the daily dosage is about 80 mg FAE to about 480 mgFAE including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 90 mg FAE to about 120 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 90 mg FAE to about 240 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 100 mg FAE to about 200 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 100 mg FAE to about 240 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 180 mg FAE to about 240 mgFAE, including all integers and fractions within the specified range. Inone embodiment, the daily dosage is about 200 mg FAE to about 240 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 360 mg FAE to about 480 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 400 mg FAE to about 480 mgFAE, including all integers and fractions within the specified range. Inanother embodiment, the daily dosage is about 480 mg FAE.

In another embodiment, the daily dosage form can comprise, but is notlimited to, a total amount of FAE of about 80 mg FAE, about 82 mg FAE,about 84 mg FAE, about 86 mg FAE, about 88 mg FAE, about 90 mg FAE,about 92 mg FAE, about 94 mg FAE, about 96 mg FAE, about 98 mg FAE,about 100 mg FAE, about 102 mg FAE, about 104 mg FAE, about 106 mg FAE,about 108 mg FAE, about 110 mg FAE, about 112 mg FAE, about 114 mg FAE,about 116 mg FAE, about 118 mg FAE, about 120 mg FAE, about 122 mg FAE,about 124 mg FAE, about 126 mg FAE, about 128 mg FAE, about 130 mg FAE,about 132 mg FAE, about 134 mg FAE, about 136 mg FAE, about 138 mg FAE,about 140 mg FAE, about 142 mg FAE, about 144 mg FAE, about 146 mg FAE,about 148 mg FAE, about 150 mg FAE, about 152 mg FAE, about 154 mg FAE,about 156 mg FAE, about 158 mg FAE, about 160 mg FAE, about 162 mg FAE,about 164 mg FAE, about 166 mg FAE, about 168 mg FAE, about 170 mg FAE,about 172 mg FAE, about 174 mg FAE, about 176 mg FAE, about 178 mg FAE,about 180 mg FAE, about 182 mg FAE, about 184 mg FAE, about 186 mg FAE,about 188 mg FAE, about 190 mg FAE, about 192 mg FAE, about 194 mg FAE,about 196 mg FAE, about 198 mg FAE, about 200 mg FAE, about 202 mg FAE,about 204 mg FAE, about 206 mg FAE, about 208 mg FAE, about 210 mg FAE,about 212 mg FAE, about 214 mg FAE, about 216 mg FAE, about 218 mg FAE,about 220 mg FAE, about 222 mg FAE, about 224 mg FAE, about 226 mg FAE,about 228 mg FAE, about 230 mg FAE, about 232 mg FAE, about 234 mg FAE,about 236 mg FAE, about 238 mg FAE, about 240 mg FAE, about 242 mg FAE,about 244 mg FAE, about 246 mg FAE, about 248 mg FAE, about 250 mg FAE,about 252 mg FAE, about 254 mg FAE, about 256 mg FAE, about 258 mg FAE,about 260 mg FAE, about 262 mg FAE, about 264 mg FAE, about 266 mg FAE,about 268 mg FAE, about 270 mg FAE, about 272 mg FAE, about 274 mg FAE,about 276 mg FAE, about 278 mg FAE, about 280 mg FAE, about 282 mg FAE,about 284 mg FAE, about 286 mg FAE, about 288 mg FAE, about 290 mg FAE,about 292 mg FAE, about 294 mg FAE, about 296 mg FAE, about 298 mg FAE,about 300 mg FAE, about 302 mg FAE, about 304 mg FAE, about 306 mg FAE,about 308 mg FAE, about 310 mg FAE, about 312 mg FAE, about 314 mg FAE,about 316 mg FAE, about 318 mg FAE, about 320 mg FAE, about 322 mg FAE,about 324 mg FAE, about 326 mg FAE, about 328 mg FAE, about 330 mg FAE,about 332 mg FAE, about 334 mg FAE, about 336 mg FAE, about 338 mg FAE,about 340 mg FAE, about 342 mg FAE, about 344 mg FAE, about 346 mg FAE,about 348 mg FAE, about 350 mg FAE, about 352 mg FAE, about 354 mg FAE,about 356 mg FAE, about 358 mg FAE, about 360 mg FAE, about 362 mg FAE,about 364 mg FAE, about 366 mg FAE, about 368 mg FAE, about 370 mg FAE,about 372 mg FAE, about 374 mg FAE, about 376 mg FAE, about 378 mg FAE,about 380 mg FAE, about 382 mg FAE, about 384 mg FAE, about 386 mg FAE,about 388 mg FAE, about 390 mg FAE, about 392 mg FAE, about 394 mg FAE,about 396 mg FAE, about 398 mg FAE, about 400 mg FAE, about 402 mg FAE,about 404 mg FAE, about 406 mg FAE, about 408 mg FAE, about 410 mg FAE,about 412 mg FAE, about 414 mg FAE, about 416 mg FAE, about 418 mg FAE,about 420 mg FAE, about 422 mg FAE, about 424 mg FAE, about 426 mg FAE,about 428 mg FAE, about 430 mg FAE, about 432 mg FAE, about 434 mg FAE,about 436 mg FAE, about 438 mg FAE, about 440 mg FAE, about 442 mg FAE,about 444 mg FAE, about 446 mg FAE, about 448 mg FAE, about 450 mg FAE,about 452 mg FAE, about 454 mg FAE, about 456 mg FAE, about 458 mg FAE,about 460 mg FAE, about 462 mg FAE, about 464 mg FAE, about 466 mg FAE,about 468 mg FAE, about 470 mg FAE, about 472 mg FAE, about 474 mg FAE,about 476 mg FAE, about 478 mg FAE, or about 480 mg FAE. The dailydosage form can contain a total amount of fumarate ester effective fortreatment of retarding the progression of, prophylaxis of delaying theonset of, amelioration of, or reducing symptoms of multiple sclerosis orpsoriasis or other neurodegenerative disorders.

In one embodiment, the amount of fumarate ester can comprise about 80 mgto about 500 mg (e.g., 80-500 mg) of fumarate ester, including allintegers and fractions within the specified range. In one embodiment,the amount can comprise, but is not limited to, about 80 mg to about 480mg FAE, including all integers and fractions within the specified range.In one embodiment, the amount of fumarate ester can comprise about 80 mgFAE to about 85 mg FAE, about 85 mg FAE to about 90 mg FAE, about 85 mgFAE to about 100 mg FAE, about 90 mg FAE to about 95 mg FAE, about 90 mgFAE to about 100 mg FAE, about 90 mg FAE, to about 105 mg FAE, about 95mg FAE to about 100 mg FAE, about 100 mg FAE to about 105 mg FAE, about100 mg FAE to about 110 mg FAE, about 100 mg FAE to about 115 mg FAE,about 100 mg FAE to about 120 mg FAE, about 100 mg FAE to about 200 mgFAE, about 100 mg FAE to about 210 mg FAE, about 100 mg FAE to about 220mg FAE, about 100 mg FAE to about 230 mg FAE, about 100 mg FAE to about240 mg FAE, about 100 mg FAE to about 400 mg FAE, about 100 mg FAE toabout 420 mg FAE, about 100 mg FAE to about 430 mg FAE, about 100 mg FAEto about 440 mg FAE, about 100 mg FAE to about 460 mg FAE, about 100 mgFAE to about 480 mg FAE, about 105 mg FAE to about 110 mg FAE, about 105mg FAE to about 115 mg FAE, about 105 mg FAE to about 120 mg FAE, about105 mg FAE to about 200 mg FAE, about 105 mg FAE to about 210 mg FAE,about 105 mg FAE to about 220 mg FAE, about 105 mg FAE to about 230 mgFAE, about 105 mg FAE to about 240 mg FAE, about 105 mg FAE to about 400mg FAE, about 105 mg FAE to about 420 mg FAE, about 105 mg FAE to about430 mg FAE, about 105 mg FAE to about 440 mg FAE, about 105 mg FAE toabout 460 mg FAE, about 105 mg FAE to about 480 mg FAE, about 110 mg FAEto about 115 mg FAE, about 110 mg FAE to about 120 mg FAE, about 110 mgFAE to about 200 mg FAE, about 110 mg FAE to about 210 mg FAE, about 110mg FAE to about 220 mg FAE, about 110 mg FAE to about 230 mg FAE, about110 mg FAE to about 240 mg FAE, about 110 mg FAE to about 400 mg FAE,about 110 mg FAE to about 420 mg FAE, about 120 mg FAE to about 430 mgFAE, about 110 mg FAE to about 440 mg FAE, about 110 mg FAE to about 460mg FAE, about 110 mg FAE to about 480 mg FAE, about 115 mg FAE to about120 mg FAE, about 115 mg FAE to about 200 mg FAE, about 115 mg FAE toabout 210 mg FAE, about 115 mg FAE to about 220 mg FAE, about 115 mg FAEto about 230 mg FAE, about 115 mg FAE to about 240 mg FAE, about 115 mgFAE to about 400 mg FAE, about 115 mg FAE to about 420 mg FAE, about 115mg FAE to about 430 mg FAE, about 115 mg FAE to about 440 mg FAE, about115 mg FAE to about 460 mg FAE, about 115 mg FAE to about 480 mg FAE,about 120 mg FAE to about 200 mg FAE, about 120 mg FAE to about 210 mgFAE, about 120 mg FAE to about 220 mg FAE, about 120 mg FAE to about 230mg FAE, about 120 mg FAE to about 240 mg FAE, about 120 mg FAE to about400 mg FAE, about 120 mg FAE to about 420 mg FAE, about 120 mg FAE toabout 430 mg FAE, about 120 mg FAE to about 440 mg FAE, about 120 mg FAEto about 460 mg FAE, about 120 mg FAE to about 480 mg FAE, about 200 mgFAE to about 210 mg FAE, about 200 mg FAE to about 220 mg FAE, about 200mg FAE to about 230 mg FAE, about 200 mg FAE to about 240 mg FAE, about200 mg FAE to about 400 mg FAE, about 200 mg FAE to about 420 mg FAE,about 200 mg FAE to about 430 mg FAE, about 200 mg FAE to about 440 mgFAE, about 200 mg FAE to about 460 mg FAE, about 200 mg FAE to about 480mg FAE, about 210 mg FAE to about 220 mg FAE, about 210 mg FAE to about230 mg FAE, about 210 mg FAE to about 240 mg FAE, about 210 mg FAE toabout 400 mg FAE, about 210 mg FAE to about 420 mg FAE, about 210 mg FAEto about 430 mg FAE, about 210 mg FAE to about 440 mg FAE, about 210 mgFAE to about 460 mg FAE, about 210 mg FAE to about 480 mg FAE, about 220mg FAE to about 230 mg FAE, about 220 mg FAE to about 240 mg FAE, about220 mg FAE to about 400 mg FAE, about 220 mg FAE to about 420 mg FAE,about 220 mg FAE to about 430 mg FAE, about 220 mg FAE to about 440 mgFAE, about 220 mg FAE to about 460 mg FAE, about 220 mg FAE to about 480mg FAE, about 230 mg FAE to about 240 mg FAE, about 230 mg FAE to about400 mg FAE, about 230 mg FAE to about 420 mg FAE, about 230 mg FAE toabout 430 mg FAE, about 230 mg FAE to about 440 mg FAE, about 230 mg FAEto about 460 mg FAE, about 230 mg FAE to about 480 mg FAE, about 240 mgFAE to about 400 mg FAE, about 240 mg FAE to about 420 mg FAE, about 240mg FAE to about 430 mg FAE, about 240 mg FAE to about 440 mg FAE, about240 mg FAE to about 460 mg FAE, about 240 mg FAE to about 480 mg FAE,about 400 mg FAE to about 420 mg FAE, about 400 mg FAE to about 430 mgFAE, about 400 mg FAE to about 440 mg FAE, about 400 mg FAE to about 460mg FAE, about 400 mg FAE to about 480 mg FAE, about 420 mg FAE to about430 mg FAE, about 420 mg FAE to about 440 mg FAE, about 420 mg FAE toabout 460 mg FAE, about 420 mg FAE to about 480 mg FAE, about 430 mg FAEto about 440 mg FAE, about 430 mg FAE to about 460 mg FAE, about 430 mgFAE to about 480 mg FAE, about 440 mg FAE to about 460 mg FAE, about 440mg FAE to about 480 mg FAE, or about 460 mg FAE to about 480 mg FAE,including all integers and fractions within the specified ranges.

In another embodiment, the effective amount of fumarate ester cancomprise, but is not limited to, about 70 mg FAE to about 480 mg FAE(e.g., 70-480 mg FAE), including all integers and fractions within thespecified range. In one aspect, the daily effective amount can comprise,but is not limited to, an effective amount of about 70 mg to about 90 mgFAE, about 75 mg to about 95 mg FAE, about 80 mg to about 100 mg FAE,about 85 mg to about 105 mg FAE, about 90 mg to about 105 mg FAE, about95 mg to about 108 mg FAE, about 100 mg to about 110 mg FAE, about 100mg to about 115 mg FAE, about 100 mg to about 120 mg FAE, about 105 mgto about 110 mg FAE, about 105 mg to about 115 mg FAE, about 105 mg toabout 120 mg FAE, about 105 mg to about 125 mg FAE, about 110 mg toabout 120 mg FAE, about 110 mg to about 125 mg FAE, about 115 mg FAE toabout 120 mg FAE, about 115 mg FAE to about 125 mg FAE, about 100 mg toabout 200 mg FAE, about 105 mg to about 210 mg FAE, about 110 mg toabout 220 mg FAE, about 115 mg FAE to about 230 mg FAE, about 120 mg toabout 240 mg FAE, about 200 mg to about 220 mg FAE, about 210 mg toabout 240 mg FAE, about 220 mg to about 250 mg FAE, about 400 mg toabout 420 mg FAE; about 400 mg to about 430 mg FAE, about 400 mg toabout 440 mg FAE, about 400 mg to about 450 mg FAE, about 400 mg toabout 460 mg FAE, about 400 mg to about 480 mg FAE, about 410 mg toabout 420 mg FAE; about 410 mg to about 430 mg FAE, about 410 mg toabout 440 mg FAE, about 410 mg to about 450 mg FAE, about 410 mg toabout 460 mg FAE, about 410 mg to about 480 mg FAE, about 420 mg toabout 430 mg FAE, about 420 mg to about 440 mg FAE, about 420 mg toabout 450 mg FAE, about 420 mg to about 460 mg FAE, about 420 mg toabout 480 mg FAE, about 425 mg to about 430 mg FAE, about 425 mg toabout 440 mg FAE; about 425 mg to about 450 mg FAE, about 425 mg toabout 460 mg FAE, about 425 mg to about 480 mg FAE, about 430 mg toabout 440 mg FAE, about 430 mg to about 450 mg FAE, about 430 mg toabout 460 mg FAE, about 430 mg to about 480 mg FAE, about 440 mg toabout 450 mg FAE, about 440 mg to about 460 mg FAE, or about 440 mg toabout 480 mg FAE, including all integers and fractions within thespecified ranges.

In one embodiment described herein, the FAE may comprise a solution orsuspension having an active pharmaceutical ingredient load (e.g., drugload) of about 1% to about 65% by weight, including all integers andfractions within the specified range. In one embodiment, the drug loadcan comprise about 12% to about 16% by weight, including all integersand fractions within the specified range. In one embodiment, the drugload can comprise about 24% to about 32% by weight, including allintegers and fractions within the specified range. In one embodiment,the drug load can comprise about 48% to about 64% by weight, includingall integers and fractions within the specified range. In oneembodiment, the drug load can comprise about 1%, about 2%, about 2.5%,about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 40%, about 50%, about 60%, about 65%,or even higher, by weight. In one embodiment, the drug load can comprise13.3%, 14.0%, 14.4%, 14.7%, 15.3%, 16.0%, 26.7%, 28.0%, 28.8%, 29.3%,30.7%, 32.0%, 53.3%, 56.0%, 57.6%, 58.7%, 61.3%, or 64.0%, each byweight. In one aspect, the drug load is about 20% by weight. In oneaspect, the drug load is about 30% by weight. In one aspect, the drugload is about 40% by weight. In one aspect, the drug load is about 50%by weight. In one aspect, the drug load is about 60% by weight. In oneaspect, the drug load is about 28% by weight. In one aspect, the drugload is about 32% by weight. In one aspect, the drug load is about 44%by weight. In one embodiment, the drug load is about 48% by weight. Inone embodiment, the drug load is about 56% by weight.

In one embodiment described herein, pharmaceutical composition cancomprise about 0.4 mmol FAE to about 4.0 mmol FAE, including allintegers and fractions within the specified range. In one embodiment,the pharmaceutical composition comprises 0.4 mmol FAE, 0.5 mmol FAE, 0.6mmol FAE, 0.7 mmol FAE, 0.8 mmol FAE, 0.9 mmol FAE, 1.0 mmol FAE, 1.1mmol FAE, 1.2 mmol FAE, 1.3 mmol FAE, 1.4 mmol FAE, 1.5 mmol FAE, 1.6mmol FAE, 1.7 mmol FAE, 1.8 mmol FAE, 1.9 mmol FAE, 2.0 mmol FAE, 2.1mmol FAE, 2.2 mmol FAE, 2.3 mmol FAE, 2.4 mmol FAE, 2.5 mmol FAE, 2.6mmol FAE, 2.7 mmol FAE, 2.8 mmol FAE, 2.9 mmol FAE, 3.0 mmol FAE, 3.1mmol FAE, 3.2 mmol FAE, 3.3 mmol FAE, 3.4 mmol FAE, 3.5 mmol FAE, 3.6mmol FAE, 3.7 mmol FAE, 3.8 mmol FAE, 3.9 mmol FAE, or 4.0 mmol FAE.

One embodiment described herein is a pharmaceutical dosage formcomprising any one of the pharmaceutical compositions described hereinfor administration to a subject having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis, comprising a therapeutically effective amount of one or morefumarate esters, wherein the administration is sufficient to achieve areduction of about 0.224 annualized relapse rate relative to baseline inthe subject without substantially inducing one or more of flushing,abdominal pain, diarrhea, and nausea in the subject; and wherein theadministration does not require titration of the pharmaceuticalcomposition.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of multiple sclerosis or psoriasis comprisingthe administration of a therapeutically effective amount of one or morefumarate esters comprising any one of the pharmaceutical compositionsdescribed herein to a subject with multiple sclerosis, wherein theadministration is sufficient to achieve a reduction of about 0.224annualized relapse rate relative to baseline in the subject withoutsubstantially inducing one or more of flushing, abdominal pain,diarrhea, and nausea in the subject. In one aspect, after administrationof any one the pharmaceutical compositions described herein, the subjectexperiences one or more of flushing, abdominal pain, diarrhea, andnausea at a rate of less than about 10%. In another aspect, the endpointmay be less than about 2%, about 5%, about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, about 45%, about 50%, or greater thanabout 50%.

Another embodiment described herein is a pharmaceutical composition anda method for treating, retarding the progression of, delaying the onsetof, prophylaxis of, amelioration of, or reducing the symptoms of ageneral autoimmune or neurodegenerative disorder, including but notlimited to multiple sclerosis or psoriasis, the method comprising theadministration of a therapeutically effective amount of one or morefumarate esters comprising any one of the pharmaceutical compositionsdescribed herein to a subject in need thereof, wherein the subjectachieves a reduction of annualized relapse rate relative to baselinewithout substantially experiencing one or more of flushing, abdominalpain, diarrhea, and nausea. In another aspect, the endpoint may be lessthan about 2%, about 5%, about 10%, about 15%, about 20%, about 25%,about 30%, about 35%, about 45%, about 50%, or greater than about 50%,relative to baseline.

Endpoints for treating multiple sclerosis using fumarate esters aredescribed in the TECFIDERA® Prescribing Information (Biogen Idec Inc.),and U.S. Patent Application Publication No. US 2014/0163100, each ofwhich is incorporated by reference herein for such teachings. Otherpharmaceutical compositions and methods for treating multiple sclerosisare described in U.S. Pat. Nos. 6,509,376; 7,320,999; 7,619,001;7,803,840; 8,399,514; 8,524,773; and 8,759,393, and International PatentApplication Publication No. WO 2013/119677, each of which isincorporated by reference herein for such teachings.

Another embodiment described herein is a pharmaceutical composition foradministration to a subject with multiple sclerosis or psoriasiscomprising a therapeutically effective amount of one or more fumarateesters, wherein the subject achieves a reduction of annualized relapserate relative to baseline without substantially experiencing one or moreof flushing, abdominal pain, diarrhea, and nausea. In one aspect thereduction of annualized relapse rate may be about 1%, about 2%, about5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%,about 45%, about 50%, or greater than about 50%.

For the treatment of multiple sclerosis (e.g., relapsing forms of MSsuch as RRMS), the dosage form administered to the subject or subject inneed thereof comprises an enteric soft capsule comprising micronizedsolid particles of a fumarate ester as the only active ingredient or incombination with one or more NSAIDS (e.g., aspirin) or leukotrienereceptor antagonists (e.g., montelukast or zafirlukast). In one aspect,the effective amount of fumarate ester is about 360 mg to about 480 mgFAE per day and the subjects can receive the effective amount, e.g.,about 80 mg to about 120 mg FAE quater in die (QID), in the form of fourcapsules a day, to be taken orally, including all integers and fractionswithin the specified ranges. In another aspect, the effective amount isabout 80 mg to about 110 mg FAE quater in die (QID). In another aspect,the effective amount is about 90 mg to about 107 mg FAE quater in die(QID). In another aspect, the effective amount is about 102 mg to about115 mg FAE quater in die (QID). In one aspect, the effective amount offumarate ester is about 360 mg to about 480 mg FAE per day and thesubjects can receive the effective amount, e.g., about 180 mg to about240 mg FAE bis in die (BID), in the form of two capsules a day, to betaken orally, including all integers and fractions within the specifiedranges. In another aspect, the effective amount is about 205 mg to about230 mg FAE BID. In a further aspect, the effective amount is about 210mg to about 225 mg FAE BID, or about 215 mg to 220 mg FAE BID. Inanother aspect, the effective amount of FAE is about 360 mg to about 480mg FAE per day and the subjects can receive the effective amount, e.g.,about 360 to about 480 mg FAE quaque die (QD), in the form of onecapsule a day, to be taken orally, including all integers and fractionswithin the specified ranges.

In another embodiment, for the treatment of multiple sclerosis the dailyeffective amount of FAE is from 80 mg FAE to 85 mg FAE, 80 mg FAE to 90mg FAE, 80 mg FAE to 95 mg FAE, 85 mg FAE to 100 mg FAE, 85 mg FAE to 90mg FAE, 85 mg FAE to 95 mg FAE, 90 mg FAE to 100 mg FAE, 90 mg FAE to105 mg FAE, 90 mg FAE to 95 mg FAE, 95 mg FAE to 100 mg FAE, 95 mg FAEto 105 mg FAE, 95 mg FAE to 110 mg FAE, 100 mg FAE to 105 mg FAE, 100 mgFAE to 110 mg FAE, 100 mg FAE to 115 mg FAE, 105 mg FAE to 110 mg FAE,105 mg FAE to 115 mg FAE, 105 mg FAE to 120 mg FAE, 110 mg FAE to 115 mgFAE, 110 mg FAE to 120 mg FAE, 110 mg FAE to 125 mg FAE, 115 mg FAE to120 mg FAE, 115 mg FAE to 125 mg FAE, 115 mg FAE to 130 mg FAE, 120 mgFAE to 125 mg FAE, 120 mg FAE to 130 mg FAE, 120 mg FAE to 135 mg FAE,125 mg FAE to 130 mg FAE, 125 mg FAE to 135 mg FAE, 125 mg FAE to 140 mgFAE, 130 mg FAE to 135 mg FAE, 130 mg FAE to 140 mg FAE, 130 mg FAE to145 mg FAE, 135 mg FAE to 140 mg FAE, 135 mg FAE to 145 mg FAE, 135 mgFAE to 150 mg FAE, 140 mg FAE to 145 mg FAE, 140 mg FAE to 150 mg FAE,140 mg FAE to 155 mg FAE, 145 mg FAE to 150 mg FAE, 145 mg FAE to 155 mgFAE, 145 mg FAE to 160 mg FAE, 150 mg FAE to 155 mg FAE, 150 mg FAE to160 mg FAE, 150 mg FAE to 165 mg FAE, 155 mg FAE to 160 mg FAE, 155 mgFAE to 165 mg FAE, 155 mg FAE to 170 mg FAE, 160 mg FAE to 165 mg FAE,160 mg FAE to 170 mg FAE, 160 mg FAE to 175 mg FAE, 165 mg FAE to 170 mgFAE, 165 mg FAE to 175 mg FAE, 165 mg FAE to 180 mg FAE, 170 mg FAE to175 mg FAE, 170 mg FAE to 180 mg FAE, 170 mg FAE to 185 mg FAE, 175 mgFAE to 180 mg FAE, 175 mg FAE to 185 mg FAE, 175 mg FAE to 190 mg FAE,180 mg FAE to 185 mg FAE, 180 mg FAE to 190 mg FAE, 180 mg FAE to 195 mgFAE, 185 mg FAE to 190 mg FAE, 185 mg FAE to 195 mg FAE, 185 mg FAE to200 mg FAE, 190 mg FAE to 195 mg FAE, 190 mg FAE to 200 mg FAE, 190 mgFAE to 205 mg FAE, 195 mg FAE to 200 mg FAE, 195 mg FAE to 205 mg FAE,195 mg FAE to 210 mg FAE, 200 mg FAE to 205 mg FAE, 200 mg FAE to 210 mgFAE, 200 mg FAE to 215 mg FAE, 205 mg FAE to 210 mg FAE, 205 mg FAE to215 mg FAE, 205 mg FAE to 220 mg FAE, 210 mg FAE to 215 mg FAE, 210 mgFAE to 220 mg FAE, 210 mg FAE to 225 mg FAE, 215 mg FAE to 220 mg FAE,215 mg FAE to 225 mg FAE, 215 mg FAE to 230 mg FAE, 220 mg FAE to 225 mgFAE, 220 mg FAE to 230 mg FAE, 220 mg FAE to 235 mg FAE, 225 mg FAE to230 mg FAE, 225 mg FAE to 235 mg FAE, 225 mg FAE to 240 mg FAE, 230 mgFAE to 235 mg FAE, 230 mg FAE to 240 mg FAE, 230 mg FAE to 245 mg FAE,235 mg FAE to 240 mg FAE, 235 mg FAE to 245 mg FAE, 235 mg FAE to 250 mgFAE, 240 mg FAE to 245 mg FAE, 240 mg FAE to 250 mg FAE, 240 mg FAE to255 mg FAE, 245 mg FAE to 250 mg FAE, 245 mg FAE to 255 mg FAE, 245 mgFAE to 260 mg FAE, 250 mg FAE to 255 mg FAE, 250 mg FAE to 260 mg FAE,250 mg FAE to 265 mg FAE, 255 mg FAE to 260 mg FAE, 255 mg FAE to 265 mgFAE, 255 mg FAE to 270 mg FAE, 260 mg FAE to 265 mg FAE, 260 mg FAE to270 mg FAE, 260 mg FAE to 275 mg FAE, 265 mg FAE to 270 mg FAE, 265 mgFAE to 275 mg FAE, 265 mg FAE to 280 mg FAE, 270 mg FAE to 275 mg FAE,270 mg FAE to 280 mg FAE, 270 mg FAE to 285 mg FAE, 275 mg FAE to 280 mgFAE, 275 mg FAE to 285 mg FAE, 275 mg FAE to 290 mg FAE, 280 mg FAE to285 mg FAE, 280 mg FAE to 290 mg FAE, 280 mg FAE to 295 mg FAE, 285 mgFAE to 290 mg FAE, 285 mg FAE to 295 mg FAE, 285 mg FAE to 300 mg FAE,290 mg FAE to 295 mg FAE, 290 mg FAE to 300 mg FAE, 290 mg FAE to 305 mgFAE, 295 mg FAE to 300 mg FAE, 295 mg FAE to 305 mg FAE, 295 mg FAE to310 mg FAE, 300 mg FAE to 305 mg FAE, 300 mg FAE to 310 mg FAE, 300 mgFAE to 315 mg FAE, 305 mg FAE to 310 mg FAE, 305 mg FAE to 315 mg FAE,305 mg FAE to 320 mg FAE, 310 mg FAE to 315 mg FAE, 310 mg FAE to 320 mgFAE, 310 mg FAE to 325 mg FAE, 315 mg FAE to 320 mg FAE, 315 mg FAE to325 mg FAE, 315 mg FAE to 330 mg FAE, 320 mg FAE to 325 mg FAE, 320 mgFAE to 330 mg FAE, 320 mg FAE to 335 mg FAE, 325 mg FAE to 330 mg FAE,325 mg FAE to 335 mg FAE, 325 mg FAE to 340 mg FAE, 330 mg FAE to 335 mgFAE, 330 mg FAE to 340 mg FAE, 330 mg FAE to 345 mg FAE, 335 mg FAE to340 mg FAE, 335 mg FAE to 345 mg FAE, 335 mg FAE to 350 mg FAE, 340 mgFAE to 345 mg FAE, 340 mg FAE to 350 mg FAE, 340 mg FAE to 355 mg FAE,345 mg FAE to 350 mg FAE, 345 mg FAE to 355 mg FAE, 345 mg FAE to 360 mgFAE, 350 mg FAE to 355 mg FAE, 350 mg FAE to 360 mg FAE, 350 mg FAE to365 mg FAE, 355 mg FAE to 360 mg FAE, 355 mg FAE to 365 mg FAE, 355 mgFAE to 370 mg FAE, 360 mg FAE to 365 mg FAE, 360 mg FAE to 370 mg FAE,360 mg FAE to 375 mg FAE, 365 mg FAE to 370 mg FAE, 365 mg FAE to 375 mgFAE, 365 mg FAE to 380 mg FAE, 370 mg FAE to 375 mg FAE, 370 mg FAE to380 mg FAE, 370 mg FAE to 385 mg FAE, 375 mg FAE to 380 mg FAE, 375 mgFAE to 385 mg FAE, 375 mg FAE to 390 mg FAE, 380 mg FAE to 385 mg FAE,380 mg FAE to 390 mg FAE, 380 mg FAE to 395 mg FAE, 385 mg FAE to 390 mgFAE, 385 mg FAE to 395 mg FAE, 385 mg FAE to 400 mg FAE, 390 mg FAE to395 mg FAE, 390 mg FAE to 400 mg FAE, 390 mg FAE to 405 mg FAE, 395 mgFAE to 400 mg FAE, 395 mg FAE to 405 mg FAE, 395 mg FAE to 410 mg FAE,400 mg FAE to 405 mg FAE, 400 mg FAE to 410 mg FAE, 400 mg FAE to 415 mgFAE, 405 mg FAE to 410 mg FAE, 405 mg FAE to 415 mg FAE, 405 mg FAE to420 mg FAE, 410 mg FAE to 415 mg FAE, 410 mg FAE to 420 mg FAE, 410 mgFAE to 425 mg FAE, 415 mg FAE to 420 mg FAE, 415 mg FAE to 425 mg FAE,415 mg FAE to 430 mg FAE, 420 mg FAE to 425 mg FAE, 420 mg FAE to 430 mgFAE, 420 mg FAE to 435 mg FAE, 425 mg FAE to 430 mg FAE, 425 mg FAE to435 mg FAE, 425 mg FAE to 440 mg FAE, 430 mg FAE to 435 mg FAE, 430 mgFAE to 440 mg FAE, 430 mg FAE to 445 mg FAE, 435 mg FAE to 440 mg FAE,435 mg FAE to 445 mg FAE, 435 mg FAE to 450 mg FAE, 440 mg FAE to 445 mgFAE, 440 mg FAE to 450 mg FAE, 440 mg FAE to 455 mg FAE, 445 mg FAE to450 mg FAE, 445 mg FAE to 455 mg FAE, 445 mg FAE to 460 mg FAE, 450 mgFAE to 455 mg FAE, 450 mg FAE to 460 mg FAE, 450 mg FAE to 465 mg FAE,455 mg FAE to 460 mg FAE, 455 mg FAE to 465 mg FAE, 455 mg FAE to 470 mgFAE, 460 mg FAE to 465 mg FAE, 460 mg FAE to 470 mg FAE, 460 mg FAE to475 mg FAE, 465 mg FAE to 470 mg FAE, 465 mg FAE to 475 mg FAE, 465 mgFAE to 480 mg FAE, 470 mg FAE to 475 mg FAE, 470 mg FAE to 480 mg FAE,or 475 mg FAE to 480 mg FAE. The effective amount can be administered inone or more doses, once, twice, three, four, or more times per day.

For the treatment of autoimmune disorders, including multiple sclerosisand psoriasis, the dosage form administered to the subject or subject inneed thereof comprises an enteric soft capsule comprising micronizedsolid particles of a fumarate ester as the only active ingredient or incombination with one or more NSAIDS (e.g., aspirin) or leukotrienereceptor antagonists (e.g., montelukast or zafirlukast). In one aspect,the effective amount of fumarate ester is about 360 mg to about 480 mgFAE per day and the subjects can receive the effective amount, e.g.,about 80 mg to about 120 mg FAE quater in die (QID), in the form of fourcapsules a day, to be taken orally, including all integers and fractionswithin the specified ranges. In one aspect, the effective amount offumarate ester is about 360 mg to about 480 mg FAE per day and thesubjects can receive the effective amount, e.g., about 180 mg to about240 mg FAE bis in die (BID), in the form of two capsules a day, to betaken orally, including all integers and fractions within the specifiedranges. In another aspect, the effective amount of fumarate ester isabout 360 mg to about 480 mg FAE per day and the subjects can receivethe effective amount, e.g., about 360 mg to about 480 mg FAE quaque die(QD), in the form of one capsule a day, to be taken orally, includingall integers and fractions within the specified ranges.

Fumarate esters can cause flushing and gastrointestinal (GI) sideeffects in some subjects. While the side effects generally subside soonafter subjects start on the treatment, in one aspect the starting doseis about 80 mg to about 120 mg FAE BID orally for the first 7 days,including all integers and fractions within the specified range. Thedose is increased to the effective dose of about 180 mg to about 240 mgFAE BID (e.g., about 360 mg to about 480 mg FAE per day), including allintegers and fractions within the specified ranges. In another aspect,the starting dose is about 180 mg to about 240 mg FAE BID orally for thefirst 7 days, including all integers and fractions within the specifiedranges. The dose is increased to the effective dose of about 360 mg toabout 480 mg FAE QD (e.g., about 360 mg to about 480 mg FAE per day),including all integers and fractions within the specified ranges. Forthose subjects who experience GI or flushing side effects, taking FAEwith food can improve tolerability. In one aspect described herein, FAEis administered after a meal. In another aspect described herein, FAE isadministered after a high-fat meal to reduce or ameliorate the one ormore symptoms of flushing, abdominal pain, diarrhea, and nausea in thesubject.

In one embodiment, the pharmaceutical compositions described herein canbe administered without titration of the pharmaceutical composition. Inone aspect, the pharmaceutical compositions can be administered withouttitration and without substantially inducing one or more of flushing,abdominal pain, diarrhea, and nausea in the subject.

In one embodiment, the pharmaceutical composition described herein doesnot elicit the flushing and gastrointestinal side effects when the doseis about 80 mg to about 120 mg FAE quater in die (QID) (e.g., 360 mg toabout 480 mg FAE per day), including all integers and fractions withinthe specified ranges. In another embodiment, the pharmaceuticalcomposition described herein does not elicit the flushing andgastrointestinal side effects when the dose is about 180 mg to about 240mg FAE bis in die (BID) (e.g., 360 mg to about 480 mg FAE per day),including all integers and fractions within the specified ranges. In oneembodiment, the pharmaceutical composition described herein does notelicit the flushing and gastrointestinal side effects when the dose isabout 360 mg to about 480 mg FAE quaque die (QD) (e.g., 360 mg to about480 mg FAE per day), including all integers and fractions within thespecified ranges.

In one embodiment, the pharmaceutical composition described herein doesnot elicit flushing and gastrointestinal side effects when the effectiveamount is about 180 mg FAE quaque die (QD) (e.g., 180 mg FAE per day).In another embodiment, the pharmaceutical composition described hereindoes not elicit the flushing and gastrointestinal side effects when theeffective amount is about 180 mg to about 240 mg FAE quaque die (QD)(e.g., 180 mg to about 240 mg FAE per day), including all integers andfractions within the specified ranges. In another embodiment, thepharmaceutical composition described herein does not elicit the flushingand gastrointestinal side effects when the effective amount is about 360mg to about 480 mg FAE quaque die (QD) (e.g., 360 mg to about 480 mg FAEper day), including all integers and fractions within the specifiedranges.

In another aspect, the administration of about 325 mg of non-entericcoated aspirin 30-minutes prior to FAE dosing can reduce the occurrenceand severity of flushing. In one aspect, subjects who experienceflushing with gastrointestinal side effects may reduce the dose to about100 mg to about 120 mg FAE BID temporarily, including all integers andfractions within the specified range. Within a month, the effective doseof about 180 mg to about 240 mg FAE BID should be resumed, including allintegers and fractions within the specified range. In another aspect,subjects who experience flushing with gastrointestinal side effects mayreduce the dose to about 180 mg to about 240 mg FAE BID temporarily,including all integers and fractions within the specified range. Withina month, the effective dose of about 360 mg to about 480 mg FAE QDshould be resumed, including all integers and fractions within thespecified range.

In one embodiment, a subject administered a FAE pharmaceuticalcomposition described herein may take one or more non-steroidalanti-inflammatory drugs (NSAID) before (for example, about 10 minutes toan hour, e.g., about 30 minutes before) taking a FAE pharmaceuticalcomposition described herein. In one embodiment, the subjectadministered a dosage form takes the one or more non-steroidalanti-inflammatory drugs to reduce flushing. In one embodiment, the oneor more non-steroidal anti-inflammatory drugs comprise aspirin,ibuprofen, naproxen, ketoprofen, celecoxib, or combinations thereof. Theone or more non-steroidal anti-inflammatory drugs can be administered inan amount of about 50 mg to about 500 mg before taking the dosage formdescribed herein. In one embodiment, a subject takes 325 mg aspirinabout 30-minutes before taking the dosage forms described herein.

In another embodiment, a subject administered a FAE pharmaceuticalcomposition described herein may take one or more leukotriene receptorantagonists. In another embodiment, a subject administered a FAEpharmaceutical composition described herein may take 10 to 20 mg ofmontelukast (Singulair®) or zafirlukast)(Accolate®).

In another embodiment described herein, subjects are orally administeredone or more non-steroidal anti-inflammatory drugs before taking thedosage form described herein exhibit the same pharmacokinetic properties(e.g., C_(max) and AUC) as subjects orally administered the dosage formdescribed herein without administering one or more non-steroidalanti-inflammatory drugs (e.g., aspirin, ibuprofen, naproxen, ketoprofen,celecoxib, or combinations thereof). The NSAID can be administered about30-minutes before taking the dosage form described herein.

In one embodiment described herein, a subject is administered one ormore soft capsules containing about 80 mg to about 480 mg FAE, one ormore times daily for a total daily dose of about 360 mg to about 480 mg,including all integers and fractions within the specified range. In oneaspect, the pharmaceutical composition comprises an immediate release,delayed release, controlled release, or extended release formulation ofa fumarate ester. In one embodiment, the matrix is a controlled releasematrix. In another embodiment, the matrix is a delayed release matrix.In another embodiment, the matrix is an extended release matrix. Inanother aspect, the pharmaceutical composition comprises an enteric softcapsule.

In one embodiment, subjects having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, are administered one or more enteric softcapsules containing about 80 mg to about 120 mg FAE, twice-daily for atotal daily dose of about 360 mg to about 480 mg, wherein the entericsoft capsule comprises solid microparticles of FAE in a matrix,including all integers and fractions within the specified ranges. In oneembodiment, the matrix is a controlled release matrix. In oneembodiment, the matrix is a delayed release matrix. In one embodiment,the matrix is an extended release matrix.

In one embodiment, subjects having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, are administered one or more enteric softcapsules containing about 180 mg to about 240 mg FAE, twice-daily for atotal daily dose of about 360 mg to about 480 mg, wherein the entericsoft capsule comprises solid microparticles of FAE in a matrix,including all integers and fractions within the specified ranges. In oneembodiment, the matrix is a controlled release matrix. In anotherembodiment, the matrix is a delayed release matrix. In anotherembodiment, the matrix is an extended release matrix.

In one embodiment, subjects having a general autoimmune orneurodegenerative disorder, including but not limited to multiplesclerosis or psoriasis, are administered an enteric soft capsulecontaining about 360 mg to about 480 mg FAE, once daily for a totaldaily dose of about 360 mg to about 480 mg, wherein the enteric softcapsule comprises solid microparticles of FAE in a matrix, including allintegers and fractions within the specified ranges. In one embodiment,the matrix is a controlled release matrix. In another embodiment, thematrix is a delayed release matrix. In another embodiment, the matrix isan extended release matrix.

Pharmacokinetics of fumarate esters, particularly DMF, are described bySheikh et al., Clinical Therapeutics 35(10): 1582-1594 (2013), which isincorporated by reference herein for such teachings.

In one aspect, the pharmaceutical composition described herein isprovided in a dosage form containing a total amount of about 80 mg toabout 120 mg of a fumarate ester, wherein subjects administered thedosage exhibit a mean plasma monomethyl fumarate C_(max) ranging fromabout 0.2 mg/L to about 2.41 mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 80 mg toabout 120 mg of a fumarate ester, wherein subjects administered thedosage exhibit a mean plasma monomethyl fumarate C_(max) ranging fromabout 0.4 mg/L to about 2.41 mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 80 mg toabout 120 mg of a fumarate ester, wherein subjects administered thedosage exhibit a mean plasma monomethyl fumarate C_(max) ranging fromabout 1.5 mg/L to about 3.4 mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 80 mg toabout 120 mg of a fumarate ester, wherein subjects administered thedosage exhibit a mean plasma monomethyl fumarate C_(max) ranging fromabout 1.03 mg/L to about 2.41 mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 80 mg toabout 120 mg of a fumarate ester, wherein subjects administered thedosage exhibit a mean plasma monomethyl fumarate C_(max) ranging fromabout 0.4 mg/L to about 0.75 mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 80 mg toabout 120 mg of a fumarate ester, wherein subjects administered thedosage exhibit a mean plasma monomethyl fumarate C_(max) ranging fromabout 0.76 mg/L to about 1.03 mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 80 mg toabout 120 mg of a fumarate ester, wherein subjects administered thedosage exhibit a mean plasma monomethyl fumarate C_(max) ranging fromabout 1.04 mg/L to about 1.75 mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 80 mg toabout 120 mg of a fumarate ester, wherein subjects administered thedosage exhibit a mean plasma monomethyl fumarate C_(max) ranging fromabout 1.75 mg/L to about 2.41 mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 80 mg toabout 120 mg of a fumarate ester, wherein subjects administered thedosage exhibit a mean plasma monomethyl fumarate C_(max) of at least 0.4mg/L, at least 0.5 mg/L, at least 0.6 mg/L, at least 0.7 mg/L, at least0.8 mg/L, at least 0.9 mg/L, at least 1 mg/L, at least 1.1 mg/L, atleast 1.2 mg/L, at least 1.3 mg/L, at least 1.4 mg/L, at least 1.5 mg/L,at least 1.6 mg/L, at least 1.7 mg/L, at least 1.8 mg/L, at least 1.9mg/L, at least 2 mg/L, at least 2.1 mg/L, at least 2.2 mg/L, at least2.3 mg/L, at least 2.4 mg/L, at least 2.5 mg/L, at least 2.6 mg/L, atleast 2.7 mg/L, at least 2.8 mg/L, at least 2.9 mg/L, at least 3 mg/L,at least 3.1 mg/L, at least 3.2 mg/L, at least 3.3 mg/L, or at least 3.4mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 80 mg to about 120 mg of a fumarateester, wherein subjects administered the dosage form four times dailyexhibit a mean plasma monomethyl fumarate AUC_(overall) ranging fromabout 1.0 h·mg/L to about 15.2 h·mg/L, including all integers andfractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 80 mg to about 120 mg of a fumarate ester, wherein subjectsadministered the dosage form four times daily exhibit a mean plasmamonomethyl fumarate AUC_(overall) ranging from about 2.01 h·mg/L toabout 5.2 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 80 mg to about 120 mg ofa fumarate ester, wherein subjects administered the dosage form fourtimes daily exhibit a mean plasma monomethyl fumarate AUC_(overall)ranging from about 1.0 h·mg/L to about 5.2 h·mg/L, including allintegers and fractions within the specified ranges. In another aspect,the composition is provided in a dosage form containing a total amountof about 80 mg to about 120 mg of a fumarate ester, wherein subjectsadministered the dosage form four times daily exhibit a mean plasmamonomethyl fumarate AUC_(overall) ranging from about 11.3 h·mg/L toabout 15.2 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 80 mg to about 120 mg ofa fumarate ester, wherein subjects administered the dosage form fourtimes daily exhibit a mean plasma monomethyl fumarate AUC_(overall)ranging from about 3.2 h·mg/L to about 11.2 h·mg/L, including allintegers and fractions within the specified ranges. In another aspect,the composition is provided in a dosage form containing a total amountof about 80 mg to about 120 mg of a fumarate ester, wherein subjectsadministered the dosage form four times daily exhibit a mean plasmamonomethyl fumarate AUC_(overall) ranging from about 5.2 h·mg/L to about11.2 h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 80 mg to about 120 mg of a fumarateester, wherein subjects administered the dosage form four times dailyexhibit a mean plasma monomethyl fumarate AUC_(overall) at least about1.0 h·mg/L, at least 1.2 h·mg/L, at least 1.4 h·mg/L, at least 1.6h·mg/L, at least 1.8 h·mg/L, at least 2.0 h·mg/L, at least 2.3 h·mg/L,at least about 2.6 h·mg/L, at least about 2.9 h·mg/L, at least 3.2h·mg/L, at least 3.5 h·mg/L, at least 3.8 h·mg/L, at least 4.1 h·mg/L,at least 4.4 h·mg/L, at least 4.7 h·mg/L, at least 5.0 h·mg/L, at least5.3 h·mg/L, at least 5.6 h·mg/L, at least 5.9 h·mg/L, at least 6.2h·mg/L, at least 6.5 h·mg/L, at least 6.8 h·mg/L, at least 7.1 h·mg/L,at least 7.4 h·mg/L, at least 7.7 h·mg/L, at least 8.0 h·mg/L, at least8.3 h·mg/L, at least 8.6 h·mg/L, at least 8.9 h·mg/L, at least 9.2h·mg/L, at least 9.5 h·mg/L, at least 9.8 h·mg/L, at least 10.1 h·mg/L,at least 10.4·h·mg/L, at least 10.7 h·mg/L, at least 11.0 h·mg/L, atleast 11.3 h·mg/L, at least 11.6 h·mg/L, at least 11.9 h·mg/L, at least12.2 h·mg/L, at least 12.5 h·mg/L, at least 12.8 h·mg/L, at least 13.1h·mg/L, at least 13.3 h·mg/L, at least 13.6 h·mg/L, at least 13.9h·mg/L, at least 14.2 h·mg/L, at least 14.5 h·mg/L, at least 14.8h·mg/L, or at least 15.2 h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 80 mg to about 120 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate AUC_(0→12h) ranging from about 0.5 h·mg/L toabout 5.5 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 80 mg to about 120 mg ofa fumarate ester, wherein subjects administered the dosage form exhibita mean plasma monomethyl fumarate AUC_(0→12h) ranging from about 0.5h·mg/L to about 2.5 h·mg/L, including all integers and fractions withinthe specified ranges. In another aspect, the composition is provided ina dosage form containing a total amount of about 80 mg to about 120 mgof a fumarate ester, wherein subjects administered the dosage formexhibit a mean plasma monomethyl fumarate AUC_(0→12h) ranging from about2.6 h·mg/L to about 5.5 h·mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 80 mg toabout 120 mg of a fumarate ester, wherein subjects administered thedosage form exhibit a mean plasma monomethyl fumarate AUC_(0→12h) of atleast about 0.5 h·mg/L, at least 1.0 h·mg/L, at least 1.2 h·mg/L, atleast 1.4 h·mg/L, at least 1.6 h·mg/L, at least 1.8 h·mg/L, at least 2.0h·mg/L, at least 2.1 h·mg/L, at least 2.2 h·mg/L, at least 2.3 h·mg/L,at least 2.4 h·mg/L, at least 2.5 h·mg/L, at least 2.6 h·mg/L, at least2.7 h·mg/L, at least 2.8 h·mg/L, at least 2.9 h·mg/L, at least 3 h·mg/L,at least 3.1 h·mg/L, at least 3.2 h·mg/L, at least 3.3 h·mg/L, at least3.4 h·mg/L, at least 3.5 h·mg/L, at least 3.6 h·mg/L, at least 3.7h·mg/L, at least 3.8 h·mg/L, at least 3.9 h·mg/L, at least 4 h·mg/L, atleast 4.1 h·mg/L, at least 4.2 h·mg/L, at least 4.3 h·mg/L, at least 4.4h·mg/L, at least 4.5 h·mg/L, at least 4.6 h·mg/L, at least 4.7 h·mg/L,at least 4.8 h·mg/L, at least 4.9 h·mg/L, at least 5 h·mg/L, at least5.1 h·mg/L, at least 5.2 h·mg/L, at least 5.3 h·mg/L, at least 5.4h·mg/L, or at least 5.5 h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 80 mg to about 120 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate AUC_(0→∞) ranging from about 0.5 h·mg/L toabout 5.6 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 80 mg to about 120 mg ofa fumarate ester, wherein subjects administered the dosage form exhibita mean plasma monomethyl fumarate AUC_(0→∞) ranging from about 0.5h·mg/L to about 2.6 h·mg/L, including all integers and fractions withinthe specified ranges. In another aspect, the composition is provided ina dosage form containing a total amount of about 80 mg to about 120 mgof a fumarate ester, wherein subjects administered the dosage formexhibit a mean plasma monomethyl fumarate AUC_(0→∞) ranging from about2.6 h·mg/L to about 5.5 h·mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 80 mg toabout 120 mg of a fumarate ester, wherein subjects administered thedosage form exhibit a mean plasma monomethyl fumarate AUC_(0→∞) of atleast about 0.5 h·mg/L, at least 1.0 h·mg/L, at least 1.2 h·mg/L, atleast 1.4 h·mg/L, at least 1.6 h·mg/L, at least 1.8 h·mg/L, at least 2h·mg/L, at least 2.1 h·mg/L, at least 2.2 h·mg/L, at least 2.3 h·mg/L,at least 2.4 h·mg/L, at least 2.5 h·mg/L, at least 2.6 h·mg/L, at least2.7 h·mg/L, at least 2.8 h·mg/L, at least 2.9 h·mg/L, at least 3 h·mg/L,at least 3.1 h·mg/L, at least 3.2 h·mg/L, at least 3.3 h·mg/L, at least3.4 h·mg/L, at least 3.5 h·mg/L, at least 3.6 h·mg/L, at least 3.7h·mg/L, at least 3.8 h·mg/L, at least 3.9 h·mg/L, at least 4 h·mg/L, atleast 4.1 h·mg/L, at least 4.2 h·mg/L, at least 4.3 h·mg/L, at least 4.4h·mg/L, at least 4.5 h·mg/L, at least 4.6 h·mg/L, at least 4.7 h·mg/L,at least 4.8 h·mg/L, at least 4.9 h·mg/L, at least 5 h·mg/L, at least5.1 h·mg/L, at least 5.2 h·mg/L, at least 5.3 h·mg/L, at least 5.4h·mg/L, or at least 5.5 h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 80 mg to about 120 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate T_(max) ranging from about 1.5 hours to about8.5 hours, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 80 mg to about 120 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate T_(max) ranging from about 1.6 hours to about2.5 hours, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 80 mg to about 120 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate T_(max) ranging from about 2.6 hours to about5 hours, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 80 mg to about 120 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate T_(max) ranging from about 5.1 hours to about7.5 hours, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 80 mg to about 120 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate T_(max) ranging from about 7.6 hours to about8.5 hours, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 240 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate T_(max) of at least 1.6 hours, at least 1.8hours, at least 2 hours, at least 2.2 hours, at least 2.4 hours, atleast 2.6 hours, at least 2.8 hours, at least 3 hours, at least 3.2hours, at least 3.4 hours, at least 3.6 hours, at least 3.8 hours, atleast 4 hours, at least 4.2 hours, at least 4.4 hours, at least 4.6hours, at least 4.8 hours, at least 5 hours, at least 5.2 hours, atleast 5.4 hours, at least 5.6 hours, at least 5.8 hours, at least 6hours, at least 6.2 hours, at least 6.4 hours, at least 6.6 hours, atleast 6.8 hours, at least 7 hours, at least 7.2 hours, at least 7.4hours, at least 7.6 hours, at least 7.8 hours, at least 8 hours, atleast 8.2 hours, or at least 8.4 hours.

In one embodiment described herein, a subject is administered a capsulecontaining about 180 mg to about 240 mg FAE, twice daily for a totaldaily dose of about 360 mg to about 480 mg, including all integers andfractions within the specified range. In one aspect, the pharmaceuticalcomposition comprises an immediate release, delayed release, controlledrelease, or extended release formulation of a fumarate ester. In anotheraspect, the pharmaceutical composition comprises an enteric softcapsule.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate C_(max) ranging from about 0.4 mg/L to about2.41 mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate C_(max) ranging from about 1.0 mg/L to about3.4 mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate C_(max) ranging from about 1.03 mg/L to about2.41 mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate C_(max) ranging from about 0.4 mg/L to about0.75 mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate C_(max) ranging from about 0.76 mg/L to about1.03 mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate C_(max) ranging from about 1.04 mg/L to about1.75 mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate C_(max) ranging from about 1.75 mg/L to about2.41 mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate C_(max) of at least 0.4 mg/L, at least 0.5mg/L, at least 0.6 mg/L, at least 0.7 mg/L, at least 0.8 mg/L, at least0.9 mg/L, at least 1 mg/L, at least 1.1 mg/L, at least 1.2 mg/L, atleast 1.3 mg/L, at least 1.4 mg/L, at least 1.5 mg/L, at least 1.6 mg/L,at least 1.7 mg/L, at least 1.8 mg/L, at least 1.9 mg/L, at least 2mg/L, at least 2.1 mg/L, at least 2.2 mg/L, at least 2.3 mg/L, at least2.4 mg/L, at least 2.5 mg/L, at least 2.6 mg/L, at least 2.7 mg/L, atleast 2.8 mg/L, at least 2.9 mg/L, at least 3 mg/L, at least 3.1 mg/L,at least 3.2 mg/L, at least 3.3 mg/L, or at least 3.4 mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form twice-daily exhibita mean plasma monomethyl fumarate AUC_(overall) ranging from about 1.0h·mg/L to about 15.2 h·mg/L, including all integers and fractions withinthe specified ranges. In another aspect, the composition is provided ina dosage form containing a total amount of about 180 mg to about 240 mgof a fumarate ester, wherein subjects administered the dosage formtwice-daily exhibit a mean plasma monomethyl fumarate AUC_(overall)ranging from about 2.01 h·mg/L to about 5.2 h·mg/L, including allintegers and fractions within the specified ranges. In another aspect,the composition is provided in a dosage form containing a total amountof about 180 mg to about 240 mg of a fumarate ester, wherein subjectsadministered the dosage form twice-daily exhibit a mean plasmamonomethyl fumarate AUC_(overall) ranging from about 1.0 h·mg/L to about5.2 h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form twice-daily exhibita mean plasma monomethyl fumarate AUC_(overall) ranging from about 11.3h·mg/L to about 15.2 h·mg/L, including all integers and fractions withinthe specified ranges. In another aspect, the composition is provided ina dosage form containing a total amount of about 180 mg to about 240 mgof a fumarate ester, wherein subjects administered the dosage formtwice-daily exhibit a mean plasma monomethyl fumarate AUC_(overall)ranging from about 4.8 h·mg/L to about 11.2 h·mg/L, including allintegers and fractions within the specified ranges. In another aspect,the composition is provided in a dosage form containing a total amountof about 180 mg to about 240 mg of a fumarate ester, wherein subjectsadministered the dosage form twice-daily exhibit a mean plasmamonomethyl fumarate AUC_(overall) at least about 1.0 h·mg/L, at least1.2 h·mg/L, at least 1.4 h·mg/L, at least 1.6 h·mg/L, at least 1.8h·mg/L, at least 2.0 h·mg/L, at least 2.3 h·mg/L, at least about 2.6h·mg/L, at least about 2.9 h·mg/L, at least 3.2 h·mg/L, at least 3.5h·mg/L, at least 3.8 h·mg/L, at least 4.1 h·mg/L, at least 4.4 h·mg/L,at least 4.7 h·mg/L, at least 5.0 h·mg/L, at least 5.3 h·mg/L, at least5.6 h·mg/L, at least 5.9 h·mg/L, at least 6.2 h·mg/L, at least 6.5h·mg/L, at least 6.8 h·mg/L, at least 7.1 h·mg/L, at least 7.4 h·mg/L,at least 7.7 h·mg/L, at least 8.0 h·mg/L, at least 8.3 h·mg/L, at least8.6 h·mg/L, at least 8.9 h·mg/L, at least 9.2 h·mg/L, at least 9.5h·mg/L, at least 9.8 h·mg/L, at least 10.1 h·mg/L, at least 10.4·h·mg/L,at least 10.7 h·mg/L, at least 11.0 h·mg/L, at least 11.3 h·mg/L, atleast 11.6 h·mg/L, at least 11.9 h·mg/L, at least 12.2 h·mg/L, at least12.5 h·mg/L, at least 12.8 h·mg/L, at least 13.1 h·mg/L, at least 13.3h·mg/L, at least 13.6 h·mg/L, at least 13.9 h·mg/L, at least 14.2h·mg/L, at least 14.5 h·mg/L, at least 14.8 h·mg/L, or at least 15.2h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate AUC_(0→12h) ranging from about 1.0 h·mg/L toabout 5.5 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 180 mg to about 240 mg ofa fumarate ester, wherein subjects administered the dosage form exhibita mean plasma monomethyl fumarate AUC_(0→12h) ranging from about 1.0h·mg/L to about 2.5 h·mg/L, including all integers and fractions withinthe specified ranges. In another aspect, the composition is provided ina dosage form containing a total amount of about 180 mg to about 240 mgof a fumarate ester, wherein subjects administered the dosage formexhibit a mean plasma monomethyl fumarate AUC_(0→12h) ranging from about2.6 h·mg/L to about 5.5 h·mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 180 mg toabout 240 mg of a fumarate ester, wherein subjects administered thedosage form exhibit a mean plasma monomethyl fumarate AUC_(0→12h) of atleast about 1.0 h·mg/L, at least 1.2 h·mg/L, at least 1.4 h·mg/L, atleast 1.6 h·mg/L, at least 1.8 h·mg/L, at least 2.0 h·mg/L, at least 2.1h·mg/L, at least 2.2 h·mg/L, at least 2.3 h·mg/L, at least 2.4 h·mg/L,at least 2.5 h·mg/L, at least 2.6 h·mg/L, at least 2.7 h·mg/L, at least2.8 h·mg/L, at least 2.9 h·mg/L, at least 3 h·mg/L, at least 3.1 h·mg/L,at least 3.2 h·mg/L, at least 3.3 h·mg/L, at least 3.4 h·mg/L, at least3.5 h·mg/L, at least 3.6 h·mg/L, at least 3.7 h·mg/L, at least 3.8h·mg/L, at least 3.9 h·mg/L, at least 4 h·mg/L, at least 4.1 h·mg/L, atleast 4.2 h·mg/L, at least 4.3 h·mg/L, at least 4.4 h·mg/L, at least 4.5h·mg/L, at least 4.6 h·mg/L, at least 4.7 h·mg/L, at least 4.8 h·mg/L,at least 4.9 h·mg/L, at least 5 h·mg/L, at least 5.1 h·mg/L, at least5.2 h·mg/L, at least 5.3 h·mg/L, at least 5.4 h·mg/L, or at least 5.5h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate AUC_(0→∞) ranging from about 1.0 h·mg/L toabout 5.6 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 180 mg to about 240 mg ofa fumarate ester, wherein subjects administered the dosage form exhibita mean plasma monomethyl fumarate AUC_(0→∞) ranging from about 1.0h·mg/L to about 2.5 h·mg/L, including all integers and fractions withinthe specified ranges. In another aspect, the composition is provided ina dosage form containing a total amount of about 180 mg to about 240 mgof a fumarate ester, wherein subjects administered the dosage formexhibit a mean plasma monomethyl fumarate AUC_(0→∞) ranging from about2.6 h·mg/L to about 5.5 h·mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 180 mg toabout 240 mg of a fumarate ester, wherein subjects administered thedosage form exhibit a mean plasma monomethyl fumarate AUC_(0→∞) of atleast about 1.0 h·mg/L, at least 1.2 h·mg/L, at least 1.4 h·mg/L, atleast 1.6 h·mg/L, at least 1.8 h·mg/L, at least 2 h·mg/L, at least 2.1h·mg/L, at least 2.2 h·mg/L, at least 2.3 h·mg/L, at least 2.4 h·mg/L,at least 2.5 h·mg/L, at least 2.6 h·mg/L, at least 2.7 h·mg/L, at least2.8 h·mg/L, at least 2.9 h·mg/L, at least 3 h·mg/L, at least 3.1 h·mg/L,at least 3.2 h·mg/L, at least 3.3 h·mg/L, at least 3.4 h·mg/L, at least3.5 h·mg/L, at least 3.6 h·mg/L, at least 3.7 h·mg/L, at least 3.8h·mg/L, at least 3.9 h·mg/L, at least 4 h·mg/L, at least 4.1 h·mg/L, atleast 4.2 h·mg/L, at least 4.3 h·mg/L, at least 4.4 h·mg/L, at least 4.5h·mg/L, at least 4.6 h·mg/L, at least 4.7 h·mg/L, at least 4.8 h·mg/L,at least 4.9 h·mg/L, at least 5 h·mg/L, at least 5.1 h·mg/L, at least5.2 h·mg/L, at least 5.3 h·mg/L, at least 5.4 h·mg/L, at least 5.5h·mg/L, or at least 5.6 h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate T_(max) ranging from about 1.5 hours to about8.5 hours, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate T_(max) ranging from about 1.6 hours to about2.5 hours, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate T_(max) ranging from about 2.6 hours to about5 hours, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate T_(max) ranging from about 5.1 hours to about7.5 hours, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 180 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate T_(max) ranging from about 7.6 hours to about8.5 hours, including all integers and fractions within the specifiedranges. In one aspect, the composition is provided in a dosage formcontaining a total amount of about 240 mg to about 240 mg of a fumarateester, wherein subjects administered the dosage form exhibit a meanplasma monomethyl fumarate T_(max) of at least 1.6 hours, at least 1.8hours, at least 2 hours, at least 2.2 hours, at least 2.4 hours, atleast 2.6 hours, at least 2.8 hours, at least 3 hours, at least 3.2hours, at least 3.4 hours, at least 3.6 hours, at least 3.8 hours, atleast 4 hours, at least 4.2 hours, at least 4.4 hours, at least 4.6hours, at least 4.8 hours, at least 5 hours, at least 5.2 hours, atleast 5.4 hours, at least 5.6 hours, at least 5.8 hours, at least 6hours, at least 6.2 hours, at least 6.4 hours, at least 6.6 hours, atleast 6.8 hours, at least 7 hours, at least 7.2 hours, at least 7.4hours, at least 7.6 hours, at least 7.8 hours, at least 8 hours, atleast 8.2 hours, or at least 8.4 hours.

In one embodiment described herein, a subject is administered a capsulecontaining about 360 to about 480 mg FAE, once daily for a total dailydose of about 360 to about 480 mg, including all integers and fractionswithin the specified ranges. In one aspect, the pharmaceuticalcomposition comprises an immediate release, delayed release, controlledrelease, or extended release formulation of a fumarate ester. In anotheraspect, the pharmaceutical composition comprises an enteric softcapsule. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 360 mg to about 480 mg of a fumarateester, wherein subjects administered the dosage form once daily exhibita mean plasma monomethyl fumarate C_(max) ranging from about 0.4 mg/L toabout 5.2 mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 360 mg to about 480 mg ofa fumarate ester, wherein subjects administered the dosage form oncedaily exhibit a mean plasma monomethyl fumarate C_(max) ranging fromabout 1.5 mg/L to about 5.2 mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 360 mg toabout 480 mg of a fumarate ester, wherein subjects administered thedosage form once daily exhibit a mean plasma monomethyl fumarate C_(max)ranging from about 0.4 mg/L to about 0.75 mg/L, including all integersand fractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 360 mg to about 480 mg of a fumarate ester, wherein subjectsadministered the dosage form once daily exhibit a mean plasma monomethylfumarate C_(max) ranging from about 0.76 mg/L to about 1.03 mg/L,including all integers and fractions within the specified ranges. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 360 mg to about 480 mg of a fumarate ester,wherein subjects administered the dosage form once daily exhibit a meanplasma monomethyl fumarate C_(max) ranging from about 1.04 mg/L to about1.75 mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 360 mg to about 480 mg of a fumarateester, wherein subjects administered the dosage form once daily exhibita mean plasma monomethyl fumarate C_(max) ranging from about 1.75 mg/Lto about 2.41 mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 360 mg to about 480 mg ofa fumarate ester, wherein subjects administered the dosage form oncedaily exhibit a mean plasma monomethyl fumarate C_(max) ranging fromabout 2.42 mg/L to about 3.5 mg/L, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 360 mg toabout 480 mg of a fumarate ester, wherein subjects administered thedosage form once daily exhibit a mean plasma monomethyl fumarate C_(max)ranging from about 3.6 mg/L to about 5.2 mg/L, including all integersand fractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 360 mg to about 480 mg of a fumarate ester, wherein subjectsadministered the dosage form once daily exhibit a mean plasma monomethylfumarate C_(max) of at least about 1.0 mg/L, at least 1.1 mg/L, at least1.2 mg/L, at least 1.3 mg/L, at least 1.4 mg/L, at least 1.5 mg/L, atleast 1.6 mg/L, at least 1.7 mg/L, at least 1.8 mg/L, at least 1.9 mg/L,at least 2.0 mg/L, at least 2.1 mg/L, at least 2.2 mg/L, at least 2.3mg/L, at least 2.4 mg/L, at least 2.5 mg/L, at least 2.6 mg/L, at least2.7 mg/L, at least 2.8 mg/L, at least 2.9 mg/L, at least 3.0 mg/L, atleast 3.1 mg/L, at least 3.2 mg/L, at least 3.3 mg/L, at least 3.4 mg/L,at least 3.5 mg/L, at least 3.6 mg/L, at least 3.7 mg/L, at least 3.8mg/L, at least 3.9 mg/L, at least 4.0 mg/L, at least 4.1 mg/L, at least4.2 mg/L, at least 4.3 mg/L, at least 4.4 mg/L, at least 4.5 mg/L, atleast 4.6 mg/L, at least 4.7 mg/L, at least 4.8 mg/L, at least 4.9 mg/L,at least 5.0 mg/L, or at least 5.1 mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 360 mg to about 480 mg of a fumarateester, wherein subjects administered the dosage form once daily exhibita mean plasma monomethyl fumarate AUC_(0→12h) ranging from about 1.0h·mg/L to about 15.5 h·mg/L, including all integers and fractions withinthe specified ranges. In another aspect, the composition is provided ina dosage form containing a total amount of about 360 mg to about 480 mgof a fumarate ester, wherein subjects administered the dosage form oncedaily exhibit a mean plasma monomethyl fumarate AUC_(0→12h) ranging fromabout 1.0 h·mg/L to about 2.5 h·mg/L, including all integers andfractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 360 mg to about 480 mg of a fumarate ester, wherein subjectsadministered the dosage form once daily exhibit a mean plasma monomethylfumarate AUC_(0→42h) ranging from about 2.6 h·mg/L to about 5.5 h·mg/L,including all integers and fractions within the specified ranges. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 360 mg to about 480 mg of a fumarate ester,wherein subjects administered the dosage form once daily exhibit a meanplasma monomethyl fumarate AUC_(0→12h) ranging from about 5.6 h·mg/L toabout 7.5 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 360 mg to about 480 mg ofa fumarate ester, wherein subjects administered the dosage form oncedaily exhibit a mean plasma monomethyl fumarate AUC_(0→12h) ranging fromabout 7.6 h·mg/L to about 10.5 h·mg/L, including all integers andfractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 360 mg to about 480 mg of a fumarate ester, wherein subjectsadministered the dosage form once daily exhibit a mean plasma monomethylfumarate AUC_(0→12h) ranging from about 10.5 h·mg/L to about 15.5h·mg/L, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 360 mg to about 480 mg of a fumarateester, wherein subjects administered the dosage form once daily exhibita mean plasma monomethyl fumarate AUC_(0→12h) of at least about 1.0h·mg/L, at least 1.2 h·mg/L, at least 1.4 h·mg/L, at least 1.6 h·mg/L,at least 1.8 h·mg/L, at least 2.0 h·mg/L, at least 2.3 h·mg/L, at least2.6 h·mg/L, at least 2.9 h·mg/L, at least 3.2 h·mg/L, at least 3.5h·mg/L, at least 3.8 h·mg/L, at least 4.1 h·mg/L, at least 4.4 h·mg/L,at least 4.7 h·mg/L, at least 5 h·mg/L, at least 5.3 h·mg/L, at least5.6 h·mg/L, at least 5.9 h·mg/L, at least 6.2 h·mg/L, at least 6.5h·mg/L, at least 6.8 h·mg/L, at least 7.1 h·mg/L, at least 7.4 h·mg/L,at least 7.7 h·mg/L, at least 8.0 h·mg/L, at least 8.3 h·mg/L, at least8.6 h·mg/L, at least 8.9 h·mg/L, at least 9.2 h·mg/L, at least 9.5h·mg/L, at least 9.8 h·mg/L, at least 10.1 h·mg/L, at least 10.4 h·mg/L,at least 10.7 h·mg/L, at least 11.0 h·mg/L, at least 11.3 h·mg/L, atleast 11.6 h·mg/L, at least 11.9 h·mg/L, at least 12.2 h·mg/L, at least12.5 h·mg/L, at least 12.8 h·mg/L, at least 13.1 h·mg/L, at least 13.4h·mg/L, at least 13.7 h·mg/L, at least 14 h·mg/L, at least 14.3 h·mg/L,at least 14.6 h·mg/L, at least 14.9 h·mg/L, at least 15.2 h·mg/L, or atleast 15.5 h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 360 mg to about 480 mg of a fumarateester, wherein subjects administered the dosage form once daily exhibita mean plasma monomethyl fumarate AUC_(0→∞) ranging from about 1.0h·mg/L to about 15.5 h·mg/L, including all integers and fractions withinthe specified ranges. In another aspect, the composition is provided ina dosage form containing a total amount of about 360 mg to about 480 mgof a fumarate ester, wherein subjects administered the dosage form oncedaily exhibit a mean plasma monomethyl fumarate AUC_(0→∞) ranging fromabout 1.5 h·mg/L to about 2.5 h·mg/L, including all integers andfractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 360 mg to about 480 mg of a fumarate ester, wherein subjectsadministered the dosage form once daily exhibit a mean plasma monomethylfumarate AUC_(0→∞) ranging from about 2.6 h·mg/L to about 5.5 h·mg/L,including all integers and fractions within the specified ranges. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 360 mg to about 480 mg of a fumarate ester,wherein subjects administered the dosage form once daily exhibit a meanplasma monomethyl fumarate AUC_(0→∞) ranging from about 5.6 h·mg/L toabout 7.5 h·mg/L, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 360 mg to about 480 mg ofa fumarate ester, wherein subjects administered the dosage form oncedaily exhibit a mean plasma monomethyl fumarate AUC_(0→∞) ranging fromabout 7.6 h·mg/L to about 11.5 h·mg/L, including all integers andfractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 360 mg to about 480 mg of a fumarate ester, wherein subjectsadministered the dosage form once daily exhibit a mean plasma monomethylfumarate AUC_(0→∞) ranging from about 10.5 h·mg/L to about 15.5 h·mg/L,including all integers and fractions within the specified ranges. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 360 mg to about 480 mg of a fumarate ester,wherein subjects administered the dosage form once daily exhibit a meanplasma monomethyl fumarate AUC_(0→∞) of at least about 1.0 h·mg/L, atleast 1.2 h·mg/L, at least 1.4 h·mg/L, at least 1.6 h·mg/L, at least 1.8h·mg/L, at least 2.0 h·mg/L, at least 2.3 h·mg/L, at least 2.6 h·mg/L,at least 2.9 h·mg/L, at least 3.2 h·mg/L, at least 3.5 h·mg/L, at least3.8 h·mg/L, at least 4.1 h·mg/L, at least 4.4 h·mg/L, at least 4.7h·mg/L, at least 5 h·mg/L, at least 5.3 h·mg/L, at least 5.6 h·mg/L, atleast 5.9 h·mg/L, at least 6.2 h·mg/L, at least 6.5 h·mg/L, at least 6.8h·mg/L, at least 7.1 h·mg/L, at least 7.4 h·mg/L, at least 7.7 h·mg/L,at least 8.0 h·mg/L, at least 8.3 h·mg/L, at least 8.6 h·mg/L, at least8.9 h·mg/L, at least 9.2 h·mg/L, at least 9.5 h·mg/L, at least 9.8h·mg/L, at least 10.1 h·mg/L, at least 10.4 h·mg/L, at least 10.7h·mg/L, at least 11.0 h·mg/L, at least 11.3 h·mg/L, at least 11.6h·mg/L, at least 11.9 h·mg/L, at least 12.2 h·mg/L, at least 12.5h·mg/L, at least 12.8 h·mg/L, at least 13.1 h·mg/L, at least 13.4h·mg/L, at least 13.7 h·mg/L, at least 14 h·mg/L, at least 14.3 h·mg/L,at least 14.6 h·mg/L, at least 14.9 h·mg/L, at least 15.2 h·mg/L, or atleast 15.5 h·mg/L.

In another aspect, the composition is provided in a dosage formcontaining a total amount of about 360 mg to about 480 mg of a fumarateester, wherein subjects administered the dosage form once daily exhibita mean plasma monomethyl fumarate T_(max) ranging from about 1.5 hoursto about 10.5 hours including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 360 mg to about 480 mg ofa fumarate ester, wherein subjects administered the dosage form oncedaily exhibit a mean plasma monomethyl fumarate T_(max) ranging fromabout 1.6 hours to about 2.5 hours, including all integers and fractionswithin the specified ranges. In another aspect, the composition isprovided in a dosage form containing a total amount of about 360 mg toabout 480 mg of a fumarate ester, wherein subjects administered thedosage form once daily exhibit a mean plasma monomethyl fumarate T_(max)ranging from about 2.6 hours to about 5 hours, including all integersand fractions within the specified ranges. In another aspect, thecomposition is provided in a dosage form containing a total amount ofabout 360 mg to about 480 mg of a fumarate ester, wherein subjectsadministered the dosage form once daily exhibit a mean plasma monomethylfumarate T_(max) ranging from about 5.1 hours to about 7.5 hours,including all integers and fractions within the specified ranges. Inanother aspect, the composition is provided in a dosage form containinga total amount of about 360 mg to about 480 mg of a fumarate ester,wherein subjects administered the dosage form once daily exhibit a meanplasma monomethyl fumarate T_(max) ranging from about 7.6 hours to about8.5 hours, including all integers and fractions within the specifiedranges. In another aspect, the composition is provided in a dosage formcontaining a total amount of about 360 mg to about 480 mg of a fumarateester, wherein subjects administered the dosage form once daily exhibita mean plasma monomethyl fumarate T_(max) ranging from about 8.6 hoursto about 10.6 hours, including all integers and fractions within thespecified ranges. In another aspect, the composition is provided in adosage form containing a total amount of about 360 mg to about 480 mg ofa fumarate ester, wherein subjects administered the dosage form oncedaily exhibit a mean plasma monomethyl fumarate T_(max) of at least 1.6hours, at least 1.8 hours, at least 2 hours, at least 2.2 hours, atleast 2.4 hours, at least 2.6 hours, at least 2.8 hours, at least 3hours, at least 3.2 hours, at least 3.4 hours, at least 3.6 hours, atleast 3.8 hours, at least 4 hours, at least 4.2 hours, at least 4.4hours, at least 4.6 hours, at least 4.8 hours, at least 5 hours, atleast 5.2 hours, at least 5.4 hours, at least 5.6 hours, at least 5.8hours, at least 6 hours, at least 6.2 hours, at least 6.4 hours, atleast 6.6 hours, at least 6.8 hours, at least 7 hours, at least 7.2hours, at least 7.4 hours, at least 7.6 hours, at least 7.8 hours, atleast 8 hours, at least 8.2 hours, at least 8.4 hours, at least 8.6hours, at least 8.8 hours, at least 9.0 hours, at least 9.2 hours, atleast 9.4 hours, at least 9.6 hours, at least 9.8 hours, at least 10hours, at least 10.2 hours, at least 10.4 hours, or at least 10.6 hours.

Another embodiment described herein is a pharmaceutical composition fortreating, prophylaxis, or amelioration of general autoimmune orneurodegenerative disorders, comprising a fumarate ester, wherein thecomposition exhibits an in vitro dissolution rate (% dissolution perminute) at pH 6.8, as described herein in any one of Drawings 2-12.

Another embodiment described herein is a pharmaceutical composition fortreating, prophylaxis, or amelioration of general autoimmune orneurodegenerative disorders, including but not limited to multiplesclerosis or psoriasis, comprising a fumarate ester, wherein thecomposition exhibits an in vitro dissolution rate comprising about 10%to about 80% dissolution after about 5 minutes to about 480 minutes atpH 6.8, including all integers and fractions within the specified rangesof dissolution and time. In another aspect, the in vitro dissolutionrate at pH 6.8 is about 50% after about 20 minutes to about 1080minutes, including all integers and fractions within the specifiedranges of dissolution and time. In one aspect, the in vitro dissolutionrate at pH 6.8 is about 50% after about 5 min, is about 50% after about10 min, about 50% after about 20 min, about 50% after about 30 min,about 50% after about 40 min, about 50% after about 50 min, about 50%after about 60 min, about 50% after about 70 min, about 50% after about80 min, about 50% after about 90 min, about 50% after about 120 min,about 50% after about 150 min, about 50% after about 180 min, about 50%after about 210 min, about 50% after about 240 min, about 50% afterabout 300 min, is about 50% after about 330 min, about 50% after about360 min, is about 50% after about 390 min, about 50% after about 420min, about 50% after about 480 min, about 50% after about 540 min, about50% after about 600 min, about 50% after about 660 min, about 50% afterabout 720 min, about 50% after about 780 min, about 50% after about 840min, about 50% after about 900 min, about 50% after about 960 min, orabout 50% after 1080 min. In another aspect, the in vitro dissolutionrate at pH 6.8 is about 50% after about 0.5 hour, about 50% after about1 hour, about 50% after about 2 hours, about 50% after about 3 hours,about 50% after about 4 hours, about 50% after about 5 hours, about 50%after about 6 hours, about 50% after about 7 hours, about 50% afterabout 8 hours, about 50% after about 9 hours, about 50% after about 10hours, about 50% after about 11 hours, about 50% after about 12 hours,about 50% after about 13 hours, about 50% after about 14 hours, about50% after about 15 hours, about 50% after about 16 hours, about 50%after about 17 hours, or about 50% after about 18 hours. In one aspect,the in vitro dissolution rate at pH 6.8 is about 50% after about 10minutes. In another aspect, the in vitro dissolution rate at pH 6.8 isabout 50% after about 20 minutes. In another aspect, the in vitrodissolution rate at pH 6.8 is about 50% after about 45 minutes. Inanother aspect, the in vitro dissolution rate at pH 6.8 is about 50%after about 60 minutes. In one aspect, the in vitro dissolution rate atpH 6.8 is about 50% after about 120 minutes. In another aspect, the invitro dissolution rate at pH 6.8 is about 50% after about 180 minutes.In another aspect, the in vitro dissolution rate at pH 6.8 is about 50%after about 240 minutes. In one aspect, the in vitro dissolution rate atpH 6.8 is about 50% after about 480 minutes.

Another embodiment described herein is a method of treating aneurological disease, neurodegenerative disease, or autoimmune diseasecomprising orally administering one or more doses of one or morefumarate esters described herein to a patient in need thereof, whereinthe administration activates or modulates one or more cellular signalingpathways. In one aspect, the autoimmune disease comprises multiplesclerosis or psoriasis and the cellular signaling pathway comprises thenuclear erythroid-derived 2-like 2 (Nrf2) dependent antioxidant responseelement (ARE) pathway. Without being bound by any theory, it is believedthat at least one aspect of the pharmacological activity of the fumarateesters described herein exert an anti-inflammatory and neuroprotectiveeffect in patients with, for example, multiple sclerosis or psoriasis,by activating the Nrf2 cellular signaling pathway. Although notcompletely understood, the Nrf2 pathway is involved in the cellularresponse to oxidative stress, which has been linked to neuronaldegeneration in multiple sclerosis and in other neurodegenerative orautoimmune diseases (e.g., HIV), see, e.g., Gao et al., Clin. Pharmacol.6:19-34 (2014), which is incorporated by reference herein for itsteachings thereof.

It is currently thought that under basal conditions, Nrf2 is sequesteredin the cytoplasm to the actin-bound Kelch-like ECH-associated protein 1(Keap1). Keap1 associates with the Cullin3 ubiquitin ligase adaptorprotein, which positions Keap1 and its substrate in proximity (e.g.,NRF2) to the E3 ubiquitin ligase Rbx1. Thus, under normal conditions,the substrate (Nrf2) is polyubiquitinated and targeted for degradation.In response to oxidative stress, Nrf2 is released from the Keap1/Nrf2complex, preventing its degradation resulting in the concommitanttranslocation of NRF2 to the nucleus and activation of ARE-mediated genetranscription. Based on this understanding, any of the non-limitingmethods for determining the activation of Nrf2 may be used that arefurther described herein. See U.S. Pat. No. 8,399,514, which isincorporated by reference herein for its teachings thereof.

Nrf2 activation may be determined by assessing the in vitro activationlevels of Nrf2 and/or Nrf2 mRNA or protein expression levels. Thesequence of the promoter region of the Nrf2 gene (−1065 to −35) isknown. In vitro Nrf2 activation may be measured using a cell modelsystem transfected or transduced with an expression construct containingthe Nrf2 promoter element described above and an artificial reportergene (e.g., luciferase or a fluorescent reporter gene (GFP, RFP, YFPetc.,). See, e.g., Chan et al., Proc. Natl. Aacd. Sci. USA93:13943-13948 (1996) and Kwak et al., Mol. Cell. Biol. 22(9):2883-2892(2002), each of which is incorporated by reference herein for theirteachings thereof. Nrf2 activation may be assessed by measuring reportergene expression in treated vs. non-treated cells using standard imagingor fluorescence quantification techniques. Alternatively, PCR (e.g.,qRT-PCR) or Northern blotting may be used to determine expression levelsof Nrf2 mRNA, or Western blotting to determine Nrf2 protein levels. See,e.g., Kwak et al., Mol. Cell. Biol. 22(9):2883-2892 (2002) and Kwak etal., Mol. Med. 7:135-145 (2001), each of which is incorporated byreference herein for their teachings thereof. Antibodies against Nrf2are can be produced by methods known in the art and are commerciallyavailable from, for example, StressGen.

In addition, Nrf2 activation may be assessed by determining thesubcellular localization and/or nuclear translocation of Nrf2 in treatedvs. non-treated cells. Such assays include cell staining, or analysis ofcytoplasmic versus nuclear cell extracts. For example, an Nrf2-greenfluorescence protein (GFP) fusion protein construct can be introducedinto cells and visualized as described in, e.g., Kraft et al., J.Neurosci. 24:1101-1112 (2004) and in Satoh et al., Proc. Natl. Aacd.Sci. USA 103(3):768-773 (2006).

Nrf2 activation may be determined through indirect measurement of theexpression levels and/or activity of one or more genes under the controlof Nrf2 in treated vs. non-treated cells. For example, the expressionlevels of NADPH dehydrogenase quinone 1 (NQO1) may be determined using,for example, qRT-PCR, Northern blotting, or Western blotting, see, e.g.,Wierinckx et al., J. Neuroimmunology. 166:132-143 (2005). Methods formeasuring enzymatic activity of NQO1, using menadione as a substrate,are described in Dinkova-Kostova et al., Proc. Natl. Aacd. Sci. USA98:3404-09 (2001).

The cell type being contacted with the one or more fumarate estersdescribed herein may comprise a neuron or a neuronal cell line, a coloncarcinoma cell line (e.g., DLD1), a neuroblastoma cell line (e.g., SkNSHor IMR32), or a primary immune cell (e.g., a monocyte or T-lymphocyte orB-lymphocyte). The cell may be a cell in culture (in vitro) or be insideof a mammal (in vivo). Alternatively, endogenous Nrf2 activation may bedetermined by measuring the levels of Nrf2 or a Nrf2 regulated gene(e.g., NQO1) in a primary cell or cell population (e.g., a monocyte,T-lymphocyte, or neuronal cell) taken from a human patient havingneurological disease, neurodegenerative disease, or autoimmune disease(e.g., multiple sclerosis or psoriasis).

It will be readily apparent to one of ordinary skill in the relevantarts that suitable modifications and adaptations to the compositions,methods, and applications described herein can be made without departingfrom the scope of any embodiments or aspects thereof. The compositionsand methods provided are exemplary and are not intended to limit thescope of any of the specified embodiments. All of the variousembodiments, aspects, and options disclosed herein can be combined inany and all variations or iterations. The scope of the compositions,formulations, methods, and processes described herein include all actualor potential combinations of embodiments, aspects, options, examples,and preferences herein described. The ratios of the mass of anycomponent of any of the formulations disclosed herein to the mass of anyother component in the formulation or to the total mass of the othercomponents in the formulation are hereby disclosed as if they wereexpressly disclosed. All patents and publications cited herein areincorporated by reference herein for the specific teachings thereof.

EXAMPLES Example 1 DMF Enteric Soft Capsule Fills

Based on results of dimethyl fumarate (DMF) solubility testing invarious lipid or lipophilic vehicles (data not shown), two formulationswere selected for further studies and encapsulated in enteric softgelatin capsules: one having polyethylene glycol and one with mediumchain mono- and diglycerides. Organic acids such as caprylic acid,lactic acid, or oleic acid, were incorporated into the matrix fill toprevent the hydrolysis of dimethyl fumarate and to retain entericproperties of the shell. Application batches of enteric soft capsuleswere prepared by rotary die encapsulation using the fill compositionsshown in Table 5.

TABLE 5 DMF Fill Compositions Capmul ® MCM Matrix PEG Matrix (A413-A)(A413-B) Ingredient mg/capsule % wt mg/capsule % wt Dimethyl Fumarate240 32.0 240 32.0 (Mean PSD: 80 μm) Capmul ® MCM 367.5 49.0 PEG 400 — —382.5 51.0 Povidone K30 52.5 7.0 37.5 5.0 Tween ® 80 75 10.0 75 10.0Lactic acid 15 2.0 15 2.0 TOTAL 750 100% 750 100%

The enteric soft capsules comprising the matrix formulations shown inTable 5 were subject to two-stage dissolution experiments in a USPApparatus II (e.g., paddle method at 100 rpm). For these experiments,the capsules were introduced in to simulated gastric fluid, 0.1 NHC1, pH1.2, for 2 hours. After 2 hours, the capsules were transferred tosimulated intestinal fluid, phosphate buffer, pH 6.8. The results areshown in FIG. 2. The results show that the capsules retain their entericproperties for at least 2 hours in simulated gastric fluid at pH 1.2.Both types of capsules released DMF shortly (˜10 minutes) after beingtransferred to simulated intestinal fluid, pH 6.8. The enteric softcapsules comprising matrices comprising PEG 400 released DMF morerapidly than those comprising Capmul® MCM (ABITEC Corp.; medium chainmono- and di-glycerides).

Example 2 Stability of the Enteric Soft Capsules Over Time

The temporal stability of the dimethyl fumarate enteric soft capsulefill formulation shown in Table 6 was assessed. A sample of DMF entericsoft capsules was subjected to accelerated aging by a 1 month ofexposure to 40° C. and 75% relative humidity conditions and thenevaluated in two-stage dissolution experiment. A second sample of DMFenteric soft capsules was subject to two-stage dissolution shortly aftermanufacturing. Both sets of enteric capsules remained intact in theacidic conditions for at least 2 hours. FIG. 3. The freshly manufacturedcapsules released DMF slightly faster than the age-accelerated capsuleswhen the pH was shifted to 6.8 (phosphate buffer).

TABLE 6 DMF Fill Composition Ingredient mg/capsule % weight Dimethylfumarate 240 32.0 (Mean PSD: 80 μm) Capmul ® MCM 367.5 49.0 Povidone K30 52.5 7.0 Tween ® 80 75 10.0 Lactic acid 15 2.0 TOTAL 750 mg 100%

Example 3 DMF Release in Enteric Soft Capsules

A developmental batch of enteric soft capsules comprising a Capmul® MCMmatrix containing particles of dimethyl fumarate (Table 6) was subjectto two-stage dissolution at pH 1.2 in simulated gastric fluid for 2hours, then the buffer was changed to phosphate buffer, pH 6.8,containing 2% Cremophor® RH 40. FIG. 4. The enteric capsules remainedintact in the acidic condition, and then began releasing DMF within 20minutes of the pH-shift to simulated intestinal fluid.

Example 4 Surfactants Affect DMF Release Rate

Enteric soft capsules were prepared with matrices comprising 10% Tween®80 (Uniqema, ICI Americas Inc; polyoxyethylene (80) sorbitan monooleate;e.g., polysorbate 80) or 10% Cremophor® RH 40 (BASF SE; polyoxyl 40hydrogenated castor oil) (Table 7) and then tested in dissolutionexperiments at pH 6.8. FIG. 5. The enteric soft capsules with fillscontaining Cremophor® released DMF much more rapidly than thosecontaining Tween® 80.

TABLE 7 DMF Fill Compositions Tween ® 80 Cremophor ® RH 40 Matrix MatrixIngredient mg/capsule % wt mg/capsule % wt Dimethyl Fumarate 240 32.0240 32.0 (Mean PSD: 80 μm) Capmul ® MCM 367.5 49.0 367.5 49.0 Povidone K30 52.5 7.0 52.5 7.0 Tween ® 80 75 10.0 — — Cremophor ® RH 40 — — 7510.0 Lactic acid 15 2.0 15 2.0 TOTAL 750 100% 750 100%

Example 5 Polyvinylpyrrolidone Concentration Affects DMF Release Rate

Enteric soft capsules prepared containing fills with of 3% or 5%concentrations of Povidone K30 (e.g., PVP; 30,000 average MW) (Table 8)were tested in dissolution experiments at pH 6.8. FIG. 6. The entericsoft capsules with matrices containing 5% Povidone K30 released DMF morerapidly at pH 6.8 than those with fills containing 3% Povidone K30.

TABLE 8 DMF Fill Compositions 3% PVP 5% PVP Ingredient mg/capsule % wtmg/capsule % wt Dimethyl Fumarate 240 32.0 240 32.0 (Mean PSD: 80 μm)Capmul ® MCM 397.5 53 382.5 51 Cremophor ® RH 40 75 10.0 75 10.0Povidone K 30 22.5 3.0 37.5 5.0 Lactic acid 15 2.0 15 2.0 TOTAL 750 100%750 100% Viscosity: 43191 Cp 122000 Cp

Based on the foregoing formulation studies, the Capmul® MCM-basedformulation was selected for further analysis. A batch was manufacturedusing the formulation below (Table 9).

TABLE 9 DMF Fill Composition Ingredient mg/capsule % weight DimethylFumarate 240 32 (Mean PSD: 80 μm) Capmul ® MCM 375 50 Cremophor ® RH 4075 10 Povidone K 30 52.5 7 Lactic acid 15 2 TOTAL 750 mg 100%

Example 6 DMF Enteric Soft Capsules are Amenable to Controlled orExtended Release

The release profile of DMF is modified by varying the enteric softcapsule shell composition or by altering the fill composition orparticle size of the active ingredient. Three different release profileswere observed under two-stage dissolution experiments. All enteric softcapsules were resistant to acid for at least 2 hours, and beginreleasing DMF upon transition to pH 6.8. FIG. 7. A release profile wasobserved in an enteric soft capsule comprising a matrix of Capmul® MCMand Cremophor® RH 40 (Table 10; Release Profile 1). A different releaseprofile was observed with an enteric soft capsule shell comprising aCapmul® MCM and Tween® 80 matrix (Table 6; Release Profile 2). Anotherrelease profile was observed with an enteric soft capsule shellcomprising a matrix of soybean oil, Tween® 80, and solid particles ofDMF having a mean particle distribution size of 148 μm (Table 11;Release Profile 3).

TABLE 10 DMF Fill Composition (P31) Ingredient mg/capsule % weightDimethyl fumarate 240 32.0 (Mean PSD: 80 μm) Capmul ® MCM 367.5 49.0Cremophor ® RH 40 75 10.0 Povidone K 30 52.5 7.0 Lactic acid 15 2.0TOTAL 750 mg 100%

TABLE 11 DMF Fill Composition (P6) Ingredient mg/capsule % weightDimethyl fumarate 240 43.6 (Mean PSD 148 μm) Soybean oil 285.25 51.9Aerosil 200 75 10.0 Tween ® 80 11 2.0 Caprylic acid 11 2.0 TOTAL 550 mg100%

Example 7 DMF Particle Size Affects Release Rate

Enteric soft capsules comprising matrices with DMF particles ofdiffering mean particle size distributions as shown in Table 12 weresubject to dissolution at pH 6.8. FIG. 8.

TABLE 12 Matrices with Varying DMF Particle Sizes Formulation A (P7) B(P8) C (P9) Ingredient mg/capsule % weight mg/capsule % weightmg/capsule % weight DMF Mean PSD: 240 43.6 — — — — 168 μm DMF Mean PSD:— — 240 43.6 — — 148 μm DMF Mean PSD: — — — — 240 43.6 90 μm PEG 400 24444.4 244 44.4 244 44.4 Povidone K30 — — — — — — Tween ® 80 55 10 55 1055 10 Caprylic acid 11 2 11 2 11 2 Lactic acid — — — — — — TOTAL 550 100550 100 550 100 Formulation D (P25) E (P15) F (P23) Ingredientmg/capsule % weight mg/capsule % weight mg/capsule % weight DMF MeanPSD: 240 34.3 — — — — 76 μm DMF Mean PSD: — — 240 28.2 240 28.2 26 μmPEG 400 355 50.7 508 59.8 482 56.8 Povidone K30 21 3 — — 26 3 Tween ® 8070 10 85 10 85 10 Caprylic acid — — 17 2 17 2 Lactic acid 14 2 — — — —TOTAL 700 100 850 100 850 100

Example 8

Enteric soft capsules comprising various matrices comprising DMFparticles having particle size distribution of d90≤90 μm were preparedand analyzed in two stage (pH 1.2 and pH 6.8) or single stage (pH 6.8)dissolution experiments (data not shown). (Tables 13-15).

TABLE 13 Various DMF Fill Compositions Formulation A (P32) B (P33) C(P34) Ingredient mg/capsule % weight mg/capsule % weight mg/capsule %weight DMF 240 32.0 240 32.0 240 32.0 PSD: d90 ≤ 90 μm Capmul ® MCM 36048.0 322.5 43.0 352.5 47.0 Cremophor ® RH 40 112.5 15.0 150 20.0 112.515.0 Lactic acid 37.5 5.0 37.5 5.0 37.5 5.0 TOTAL 750 100 750 100 750100 D (P35) E (P37) F (P38) Ingredient mg/capsule % weight mg/capsule %weight mg/capsule % weight DMF 240 32.0 240 32.0 240 32.0 PSD: d90 ≤ 90μm Capmul ® MCM 315 42.0 360 48.0 360 48.0 Cremophor ® RH 40 150 20.0 7510.0 75 10.0 Lactic acid 37.5 5.0 37.5 5.0 37.5 5.0 Povidone K 30 7.51.0 — — — — PEG 400 — — 37.5 5.0 — — Polypropylene glycol — — — — 37.55.0 TOTAL 750 100 750 100 750 100 G (P39) H (P41) I (P43) Ingredientmg/capsule % weight mg/capsule % weight mg/capsule % weight DMF 240 28.2240 28.2 240 28.2 PSD: d90 ≤ 90 μm Capmul ® MCM 482.5 56.8 397.5 46.8397.5 46.8 Cremophor ® RH 40 85 10.0 85 10.0 — — Lactic acid 42.5 5.042.5 5.0 42.5 5.0 Labrasol ® — — 85 10.0 170 20.0 TOTAL 850 100 850 100850 100

TABLE 14 Various DMF Fill Compositions Formulation A (P44) B (P45) C(P46) Ingredient mg/capsule % weight mg/capsule % weight mg/capsule %weight DMF 240 28.2 240 28.2 240 28.2 PSD: d90 ≤ 90 μm Capmul ® MCM 37243.8 355 41.8 329.5 38.8 Cremophor ® RH 40 85 10.0 85 10.0 85 10.0Lactic acid 42.5 5.0 42.5 5.0 42.5 5.0 Labrasol ® 85 10.0 85 10.0 8510.0 Povidone K 30 25.5 3.0 — — 25.5 3.0 Mannitol — — 42.5 5.0 42.5 5.0TOTAL 850 100 850 100 850 100 D (P47) E (P48) F (P49) Ingredientmg/capsule % weight mg/capsule % weight mg/capsule % weight DMF 240 28.2240 28.2 240 28.2 PSD: d90 ≤ 90 μm Capmul ® MCM 384.75 45.3 284.19533.43 312.5 36.76 Cremophor ® RH 40 85 10.0 85 10.0 85 10.0 Lactic acid42.5 5.0 42.5 5.0 42.5 5.0 Povidone K 30 12.75 1.5 — — — — Labrasol ® —— 85 10.0 85 10.0 PEG 3350 85 10.0 113.305 13.33 85 10.00 TOTAL 850 100850 100 850 100 G (P50) H (P51) I (P52) Ingredient mg/capsule % weightmg/capsule % weight mg/capsule % weight DMF 240 28.2 240 28.2 240 28.2PSD: d90 ≤ 90 μm Capmul ® MCM 333.75 39.26 287 33.76 333.75 39.26Cremophor ® RH 40 85 10.0 85 10.00 85 10.00 Lactic acid 42.5 5.0 42.55.0 42.5 5.0 Labrasol ® 85 10.0 85 10.0 85 10.00 PEG 3350 63.75 7.50 — —— — Povidone K 17 — — 25.5 3.00 — — Mannitol — — 85 10.00 — —Crospovidone-CL — — — — 63.75 7.50 TOTAL 850 100 850 100 850 100

TABLE 15 Various DMF Fill Compositions Formulation A (P53) B (P54) C(P55) Ingredient mg/capsule % weight mg/capsule % weight mg/capsule %weight DMF 240 28.24 240 28.24 240 28.24 PSD: d90 ≤ 90 μm Capmul ® MCM397.5 46.76 397.5 46.76 390.7 45.96 Cremophor ® RH 40 85 10.00 85 10.0085 10.00 Lactic acid 42.5 5.00 42.5 5.00 42.5 5.00 PEG 3350 85 10.00 — —— — PEG 400 — — — — 42.5 5.00 Lutrol ® F 68 — — 85 10.00 — — Sodiumlauryl sulfate — — — — 49.3 5.80 TOTAL 850 100 850 100 850 100 D (P56) E(P57) F (P58) Ingredient mg/capsule % weight mg/capsule % weightmg/capsule % weight DMF 240 28.24 240 28.24 240 28.24 PSD: d90 ≤ 90 μmCapmul ® MCM 355 41.76 363.5 42.76 355 41.76 Cremophor ® RH 40 85 10.0085 10.00 85 10.00 Lactic acid 42.5 5.00 42.5 5.00 42.5 5.00 PEG 400 8510.00 85 10.00 85 10.00 Crospovidone CL 42.5 5.00 — — — — CrospovidoneCL-F — — 34 4.00 — — Crospovidone CL-M — — — — 42.5 5.00 TOTAL 850 100850 100 850 100 G (P59) H (P60) I (P61) Ingredient mg/capsule % weightmg/capsule % weight mg/capsule % weight DMF 240 28.24 240 28.24 24028.24 PSD: d90 ≤ 90 μm Capmul ® MCM 312.5 36.76 355 41.76 329.5 38.76Cremophor ® RH 40 85 10.00 85 10.00 85 10.00 Lactic acid 42.5 5.00 42.55.00 42.5 5.00 Labrasol ® 85 10.00 85 10.00 85 10.00 Pearlitol ® Flash85 10.00 — — 42.5 5.00 Croscarmellose — — 42.5 5.00 25.5 3.00 SodiumTOTAL 850 100 850 100 850 100

Example 9 Capsule Shell Thickness Affects Release Rate

Application batches of enteric soft capsules with shell thicknesses of0.028 inches or 0.033 inches were prepared comprising DMF particleshaving particle size distributions of d90≤90 μm in various matrices(Table 16) and analyzed in two stage (pH 1.2 and pH 6.8) dissolutionexperiments (FIG. 9).

TABLE 16 DMF Fill Compositions A (APP021214) B (APP020714) (0.028 inchribbon) (0.033 inch ribbon) Ingredient mg/capsule % wt mg/capsule % wtDimethyl Fumarate 240 28.2 240 28.2 PSD: d90 ≤ 90 μm Capmul ® MCM 44051.8 465.5 54.8 Cremophor ® RH 40 85 10.0 85 10.0 Povidone K30 42.5 5.042.5 5.0 PEG 400 — — 42.5 5.0 Crospovidone-CL 17 2.0 — — TOTAL 850 100%850 100% C (APP022414-A) D (APP022414-B) (0.028 inch ribbon) (0.028 inchribbon) Ingredient mg/capsule % wt mg/capsule % wt Dimethyl Fumarate 24028.24 240 28.24 PSD: d90 ≤ 90 μm Capmul ® MCM 312.5 36.76 312.5 36.76Cremophor ® RH 40 85 10.0 85 10.0 Povidone K30 42.5 5.0 42.5 5.0 PEG 600127.5 15.0 — — Crospovidone-CL 42.5 5.0 — — Labrasol ® — — 85 10.0Pearlitol ® Flash — — 85 10.0 TOTAL 850 100% 850 100%

Example 10

A GMP batch of enteric soft capsules (0.038-inch shell thickness)comprising DMF particles having a particle size distribution of PSD:d90≤90 μm was prepared with the matrix composition shown in Table 17 andanalyzed in two stage (pH 1.2 and pH 6.8) dissolution experiments (FIG.10) and compared to application batches (Table 15).

TABLE 17 GMP DMF Fill Composition Ingredient mg/capsule % weightDimethyl fumarate 240 32.0 PSD: d90 ≤ 90 μm Capmul ® MCM 375 50.0Cremophor ® RH 40 75 10.0 Povidone K 30 22.5 3.0 Lactic acid 37.5 5.0TOTAL 750 mg 100%

Example 11 Povidone K30 and PEG 600 Affect DMF Release Rate

DMF matrices were prepared with and without Povidone K30 or PEG 600(Table 18) and analyzed in single stage (pH 6.8) dissolution experiments(FIG. 11).

TABLE 18 DMF Fill Compositions A (P62) B (P63) Ingredient mg/capsule %weight mg/capsule % weight Dimethyl fumarate 240 28.2 240 28.24 PSD: d90≤ 90 μm Capmul ® MCM 482.5 56.8 384.75 45.26 Cremophor ® RH 40 85 10.085 10.00 Povidone K 30 — — 12.75 1.50 PEG 600 — — 85 10.00 Lactic acid42.5  5.0 42.5 5.0 TOTAL 850 mg 100% 850 mg 100% C (P64) D (P65)Ingredient mg/capsule % weight mg/capsule % weight Dimethyl fumarate 24028.24 240 28.24 PSD: d90 ≤ 90 μm Capmul ® MCM 457 53.76 372 43.76Cremophor ® RH 40 85 10.00 85 10.00 Povidone K 30 25.5 3.00 25.5 3.00PEG 600 — — 85 10.00 Lactic acid 42.5 5.00 42.5 5.00 TOTAL 850 mg 100%850 mg 100%

Example 12

A batch of enteric soft capsules (0.038 inch shell thickness) comprisingDMF particles having particle size distribution of PSD: d90≤90 μm wasprepared with the matrix composition shown in Table 19 and analyzed intwo stage (pH 1.2 and pH 6.8) dissolution experiments (FIG. 12). Thisexample provides a lower dose of DMF (120 mg) compared with that shownin Table 6 (240 mg).

TABLE 19 DMF Fill Composition Ingredient mg/capsule % weight Dimethylfumarate 120 28.2 PSD: d90 ≤ 90 μm Capmul ® MCM 228.5 53.8 Cremophor ®RH 40 42.5 10.0 Povidone K 30 12.75 3.0 Lactic acid 21.25 5.0 TOTAL 425mg 100%

Example 13

A batch of enteric soft capsules (0.038 inch shell thickness) comprisingmonomethyl fumarate (MMF) particles having particle size distribution ofPSD: d90≤90 μm was prepared with the matrix composition shown in Table20. This example provides MMF (240 mg).

TABLE 20 MMF Fill Composition Ingredient mg/capsule % weight Monomethylfumarate 240 28.2 PSD: d90 ≤ 90 μm Capmul ® MCM 457 53.8 Cremophor ® RH40 85 10.0 Povidone K 30 25.5 3.0 Lactic acid 42.5 5.0 TOTAL 850 mg 100%

Example 14

A batch of enteric soft capsules (0.038 inch shell thickness) comprisingmonomethyl fumarate (MMF) particles having particle size distribution ofPSD: d90≤90 μm was prepared with the matrix composition shown in Table21. This example provides MMF (480 mg).

TABLE 21 MMF Fill Composition Ingredient mg/capsule % weight Monomethylfumarate 480    48-56.4 PSD: d90 ≤ 90 μm Capmul ® MCM 216-470  25.5-47Cremophor ® RH 40 7.3-120  0.85-12 Povidone K 30 7.3-50  0.85-5  Lacticacid 21.7-50   2.55-5  TOTAL 850 mg-1000 mg 100%

Example 15

Enteric soft capsules comprising particles of dimethyl fumarate,monomethyl fumarate, or a combination thereof having particle sizedistribution of PSD: d90≤90 μm can be prepared with an 850 mg matrix inthe compositions shown in Table 22. This example provides DMF or MMF ina QD formulation (˜480 mg).

TABLE 22 DMF or MMF 850 mg Fill Compositions Percent Weight (%)Ingredient EX1 EX2 EX3 EX4 EX5 EX6 Dimethyl fumarate or Monomethyl 56.456.4 56.4 56.4 56.4 56.4 fumarate PSD: d90 ≤ 90 μm Capmul ® MCM 30.639.95 28.9 28.9 25.5 32.7 Cremophor ® RH 40 8.5 0.85 8.5 8.5 10.2 6.1Povidone K 30 0.85 0.85 2.55 2.55 4.25 1.8 Lactic acid 4.25 2.55 4.254.25 4.25 3.0 TOTAL 100 100 100 100 100 100

Example 16

Enteric soft capsules comprising particles of dimethyl fumarate,monomethyl fumarate, or a combination thereof having particle sizedistribution of PSD: d90≤90 μm can be prepared with a 1000 mg matrix inthe compositions shown in Table 23. This example provides DMF or MMF ina QD formulation (˜480 mg).

TABLE 23 DMF or MMF 1000 mg Fill Compositions Percent Weight (%)Ingredient EX1 EX2 EX3 EX4 EX5 EX6 Dimethyl fumarate or 48 48 48 48 4848 Monomethyl fumarate PSD: d90 ≤ 90 μm Capmul ® MCM 44 36 47 34 34 38.9Cremophor ® RH 40 2 10 1 10 10 7.2 Povidone K 30 1 1 1 3 3 2.2 Lacticacid 5 5 3 5 5 3.6 TOTAL 100 100 100 100 100 100

Example 17 Stability of the Enteric Soft Capsules Over Time

The temporal stability of the dimethyl fumarate enteric soft capsulepharmaceutical composition shown in Table 24 was assessed under threeICH conditions. A sample of DMF enteric soft capsules was subject tochemical analysis and two-stage dissolution shortly after manufacturing(T₀). Samples of DMF enteric soft capsules were subjected to RoomTemperature Conditions (25° C. and 60% relative humidity) for 1 month,2, months, 3 months, and 6 months. Other samples of DMF enteric softcapsules were subjected to Intermediate Conditions (30° C. and 65%relative humidity) for 1 month, 2 months, and 3 months. Additionalsamples of DMF enteric soft capsules were subjected to AcceleratedConditions (40° C. and 75% relative humidity) for 1 month and 2 months.After the designated incubation period, the capsules were chemicallyanalyzed and evaluated in two-stage dissolution experiments at pH 1.2and 6.8 as described herein if conditions permitted (i.e., non-leakingcapsules). Two-stage dissolution results for DMS enteric soft capsulesat T₀, and after 3- and 6-months at Room Temperature Conditions (25° C.and 60% RH) are shown in FIG. 13.

TABLE 24 GMP DMF Fill Composition Ingredient mg/capsule % weightDimethyl fumarate 240 32.0 PSD: d90 ≤ 90 μm Capmul ® MCM 375 50.0Cremophor ® RH 40 75 10.0 Povidone K 30 22.5 3.0 Lactic acid 37.5 5.0TOTAL 750 mg 100%

TABLE 25 GMP DMF Stability Initial 25° C., 60% Relative Humidity T₀ 1 M2 M 3 M 6 M Assay 101.2% 101.0% 102.4% 101.25 98.8% Degradation ProductsMonomethyl Fumarate 0.14% 0.13% 0.14% 0.16% 0.18% RRT 0.74 ND ND 0.07%0.09% 0.18% RRT 1.61 0.05% ND ND ND ND RRT 2.18 ND ND ND <0.05% 0.09%Total Degradation Products 0.19% 0.13% 0.21% 0.25% 0.45% 30° C., 65%Relative Humidity 40° C., 75% Rel. Humid. 1 M 2 M 3 M 1 M 2 M Assay100.1% 99.4% 99.5% 99.3% 113.1%* Degradation Products MonomethylFumarate 0.14% 0.17% 0.22% 0.22% 0.26% RRT 0.74 0.14% 0.22% 0.28% 0.3%0.46% RRT 1.61 0.06% 0.11% 0.14% 0.15% 0.35% RRT 2.18 0.34% 0.5% 0.64%0.67% 1.07% Total Degradation Products 0.14% 0.17% 0.22% 0.22% 0.26%*Data were collected on fill extracted from leaking capsules. Note:Leaking capsules were observed at the 2- and 3-month time points for theaccelerated condition (40° C., 75% RH). This was expected for theenteric soft gelatin capsules. The intermediate condition (30° C., 65%RH) and long-term condition (25° C., 60% RH) will be assessed at the12-month and 24-month time points to assess chemical stability.

Example 18

Fill compositions with increasing amounts of one or more fumarate esters(e.g., dimethyl fumarate, monomethyl fumarate, or a combination thereofranging from about 0.5 mmol to about 4.0 mmol) having a particle sizedistribution of PSD: d90≤100 μm in a 750 mg fill are shown in Table 26.Millimole values for DMF or MMF (shaded rows) specify the millimoles ofthe respective species at the specified mass (mg). These fillcompositions may be encapsulated by any of the capsule shellcompositions (e.g., an enteric soft capsule shell) as described herein.In one embodiment, the one or more fumarate esters comprise about 0.5mmol to about 3.7 mmol FAE. In one embodiment, the fumarate ester (FAE)comprises DMF. In another embodiment, the fumarate ester comprises MMF.In another embodiment, the fumarate ester comprises MMF, DMF, or acombination thereof.

TABLE 26 Fumarate Ester 750 mg Fill Compositions Ingredient EX1 EX2 EX3EX4 EX5 EX6 mg/capsule Fumarate Ester PSD: d90 ≤ 100 μm 80 85 90 95 97100 mmol DMF 0.56 0.59 0.62 0.66 0.67 0.69 mmol MMF 0.61 0.65 0.69 0.730.75 0.77 Capmul ® MCM 535 530 525 520 518 515 Cremophor ® RH 40 75 7575 75 75 75 Povidone K 30 22.5 22.5 22.5 22.5 22.5 22.5 Lactic acid 37.537.5 37.5 37.5 37.5 37.5 TOTAL 750 750 750 750 750 750 Ratio FAE to Fill0.12 0.13 0.14 0.15 0.15 0.15 Percent Weight (%) Fumarate Ester PSD: d90≤ 100 μm 10.7 11.3 12 12.7 12.9 13.3 Capmul ® MCM 71.3 70.7 70 69.3 69.168.7 Cremophor ® RH 40 10 10 10 10 10 10 Povidone K 30 3 3 3 3 3 3Lactic acid 5 5 5 5 5 5 TOTAL 100 100 100 100 100 100 Ingredient EX7 EX8EX9 EX10 EX11 EX12 mg/capsule Fumarate Ester PSD: d90 ≤ 100 μm 105 107108 110 115 120 mmol DMF 0.73 0.74 0.75 0.76 0.80 0.83 mmol MMF 0.810.82 0.83 0.85 0.88 0.92 Capmul ® MCM 510 508 507 505 500 495Cremophor ® RH 40 75 75 75 75 75 75 Povidone K 30 22.5 22.5 22.5 22.522.5 22.5 Lactic acid 37.5 37.5 37.5 37.5 37.5 37.5 TOTAL 750 750 750750 750 750 Ratio FAE to Fill 0.16 0.17 0.17 0.17 0.18 0.19 PercentWeight (%) Fumarate Ester PSD: d90 ≤ 100 μm 14 14.3 14.4 14.7 15.3 16Capmul ® MCM 68 67.7 67.6 67.3 66.7 66 Cremophor ® RH 40 10 10 10 10 1010 Povidone K 30 3 3 3 3 3 3 Lactic acid 5 5 5 5 5 5 TOTAL 100 100 100100 100 100 Ingredient EX13 EX14 EX15 EX16 EX17 EX18 mg/capsule FumarateEster PSD: d90 ≤ 100 μm 160 170 180 190 194 200 mmol DMF 1.11 1.18 1.251.32 1.35 1.39 mmol MMF 1.23 1.31 1.38 1.46 1.49 1.54 Capmul ® MCM 455445 435 425 421 415 Cremophor ® RH 40 75 75 75 75 75 75 Povidone K 3022.5 22.5 22.5 22.5 22.5 22.5 Lactic acid 37.5 37.5 37.5 37.5 37.5 37.5TOTAL 750 750 750 750 750 750 Ratio FAE to Fill 0.27 0.29 0.32 0.34 0.350.36 Percent Weight (%) Fumarate Ester PSD: d90 ≤ 100 μm 21.3 22.7 2425.3 25.9 26.7 Capmul ® MCM 60.7 59.3 58 56.7 56.1 55.3 Cremophor ® RH40 10 10 10 10 10 10 Povidone K 30 3 3 3 3 3 3 Lactic acid 5 5 5 5 5 5TOTAL 100 100 100 100 100 100 Ingredient EX19 EX20 EX21 EX22 EX23 EX24mg/capsule Fumarate Ester PSD: d90 ≤ 100 μm 210 214 216 220 230 240 mmolDMF 1.46 1.48 1.50 1.53 1.60 1.67 mmol MMF 1.61 1.64 1.66 1.69 1.77 1.84Capmul ® MCM 405 401 399 395 385 375 Cremophor ® RH 40 75 75 75 75 75 75Povidone K 30 22.5 22.5 22.5 22.5 22.5 22.5 Lactic acid 37.5 37.5 37.537.5 37.5 37.5 TOTAL 750 750 750 750 750 750 Ratio FAE to Fill 0.39 0.400.40 0.42 0.44 0.47 Percent Weight (%) Fumarate Ester PSD: d90 ≤ 100 μm28 28.5 28.8 29.3 30.7 32 Capmul ® MCM 54 53.5 53.2 52.7 51.3 50Cremophor ® RH 40 10 10 10 10 10 10 Povidone K 30 3 3 3 3 3 3 Lacticacid 5 5 5 5 5 5 TOTAL 100 100 100 100 100 100 Ingredient EX25 EX26 EX27EX28 EX29 EX30 mg/capsule Fumarate Ester PSD: d90 ≤ 100 μm 320 340 360380 388 400 mmol DMF 2.22 2.36 2.50 2.64 2.69 2.78 mmol MMF 2.46 2.612.77 2.92 2.98 3.07 Capmul ® MCM 295 275 255 235 227 215 Cremophor ® RH40 75 75 75 75 75 75 Povidone K 30 22.5 22.5 22.5 22.5 22.5 22.5 Lacticacid 37.5 37.5 37.5 37.5 37.5 37.5 TOTAL 750 750 750 750 750 750 RatioFAE to Fill 0.74 0.83 0.92 1.03 1.07 1.14 Percent Weight (%) FumarateEster PSD: d90 ≤ 100 μm 42.7 45.3 48 50.7 51.7 53.3 Capmul ® MCM 39.336.7 34 31.3 30.3 28.7 Cremophor ® RH 40 10 10 10 10 10 10 Povidone K 303 3 3 3 3 3 Lactic acid 5 5 5 5 5 5 TOTAL 100 100 100 100 100 100Ingredient EX31 EX32 EX33 EX34 EX35 EX36 mg/capsule Fumarate Ester PSD:d90 ≤ 100 μm 420 428 432 440 460 480 mmol DMF 2.91 2.97 3.00 3.05 3.193.33 mmol MMF 3.23 3.29 3.32 3.38 3.54 3.69 Capmul ® MCM 195 187 183 175155 135 Cremophor ® RH 40 75 75 75 75 75 75 Povidone K 30 22.5 22.5 22.522.5 22.5 22.5 Lactic acid 37.5 37.5 37.5 37.5 37.5 37.5 TOTAL 750 750750 750 750 750 Ratio FAE to Fill 0.74 0.83 0.92 1.03 1.07 1.14 PercentWeight (%) Fumarate Ester PSD: d90 ≤ 100 μm 56 57.1 57.6 58.7 61.3 64Capmul ® MCM 26 24.9 24.4 23.3 20.7 18 Cremophor ® RH 40 10 10 10 10 1010 Povidone K 30 3 3 3 3 3 3 Lactic acid 5 5 5 5 5 5 TOTAL 100 100 100100 100 100

Example 19

Fill compositions having one or more fumarate esters (e.g., dimethylfumarate, monomethyl fumarate, or a combination thereof ranging fromabout 0.5 mmol to about 3.5 mmol) having a particle size distribution ofPSD: d90≤100 μm with a constant weight ratio of fumarate ester to fill(e.g., about 0.40) are shown in Table 27. Millimole values for DMF orMMF (shaded rows) specify the millimoles of the respective species atthe specified mass (mg). These fill compositions may be encapsulated byany of the capsule shell compositions (e.g., an enteric soft capsuleshell) as described herein. In one embodiment, the fumarate estercomprises DMF. In another embodiment, the fumarate ester comprises MMF.In another embodiment, the fumarate ester comprises MMF, DMF, or acombination thereof.

TABLE 27 Fumarate Ester Fill Compositions Percent Weight (%) mg/capsuleIngredient EX1-EX4 EX1 EX2 EX3 EX4 Fumarate Ester 28.5 80 85 160 170PSD: d90 ≤ 100 μm mmol DMF N/A 0.56 0.59 1.11 1.18 mmol MMF N/A 0.610.65 1.23 1.31 Capmul ® MCM 53.5 150 159 300 318 Cremophor ® RH 40 10 2829.8 56 59.5 Povidone K 30 3 8.4 8.9 16.8 17.9 Lactic acid 5 14 14.9 2829.8 TOTAL 100 280 298 560 595 Percent Weight (%) mg/capsule IngredientEX5-EX8 EX5 EX6 EX7 EX8 Fumarate Ester 28.5 90 95 180 190 PSD: d90 ≤ 100μm mmol DMF N/A 0.62 0.66 1.25 1.32 mmol MMF N/A 0.69 0.73 1.38 1.46Capmul ® MCM 53.5 169 178 337 356 Cremophor ® RH 40 10 31.5 33.3 63 66.5Povidone K 30 3 9.5 10 18.9 20 Lactic acid 5 15.8 16.6 31.5 33.3 TOTAL100 315 333 630 665 Percent Weight (%) mg/capsule Ingredient EX9-EX12EX9 EX10 EX11 EX12 Fumarate Ester 28.5 100 107 200 214 PSD: d90 ≤ 100 μmmmol DMF N/A 0.69 0.74 1.39 1.48 mmol MMF N/A 0.77 0.82 1.54 1.64Capmul ® MCM 53.5 187 201 375 401 Cremophor ® RH 40 10 35 37.5 70.1 75Povidone K 30 3 10.5 11.3 21 22.5 Lactic acid 5 17.5 18.8 35.1 37.5TOTAL 100 350 375 701 750 Percent Weight (%) mg/capsule IngredientEX13-EX16 EX17 EX18 EX19 EX20 Fumarate Ester 28.5 105 110 210 220 PSD:d90 ≤ 100 μm mmol DMF N/A 0.73 0.76 1.46 1.53 mmol MMF N/A 0.81 0.851.61 1.69 Capmul ® MCM 53.5 197 206 393 412 Cremophor ® RH 40 10 36.838.5 73.5 77.0 Povidone K 30 3 11.0 11.6 22.1 23.1 Lactic acid 5 18.419.3 36.8 38.5 TOTAL 100 368 385 735 770 Percent Weight (%) mg/capsuleIngredient EX13-EX16 EX17 EX18 EX19 EX20 Fumarate Ester 28.5 115 120 230240 PSD: d90 ≤ 100 μm mmol DMF N/A 0.80 0.83 1.60 1.67 mmol MMF N/A 0.880.92 1.77 1.84 Capmul ® MCM 53.5 215 225 431 449 Cremophor ® RH 40 1040.3 42.0 80.5 84.0 Povidone K 30 3 12.1 12.6 24.2 25.2 Lactic acid 520.1 21.0 40.3 42.0 TOTAL 100 403 420 805 840 Percent Weight (%)mg/capsule Ingredient EX13-EX16 EX13 EX14 EX15 EX16 Fumarate Ester 28.5350 375 400 428 PSD: d90 ≤ 100 μm mmol DMF N/A 2.42 2.6 2.78 2.97 mmolMMF N/A 2.68 2.88 3.07 3.29 Capmul ® MCM 53.5 655 702 750 802Cremophor ® RH 40 10 123 131 140 150 Povidone K 30 3 36.8 39.4 42.1 45Lactic acid 5 61.3 65.6 70.1 75 TOTAL 100 1225 1313 1402 1500

Example 20

A batch of enteric soft capsules (0.038-inch shell thickness) comprisingBSL-11 particles having particle size distribution of PSD: d90≤90 μmwere prepared with the matrix composition shown in Table 28.

TABLE 28 BLS-11 Fill Composition Fill Ingredients Percent Weight (%)Mass/capsule (mg) BLS-11, PSD: d90 ≤ 90 μm 28.50 214 Capmul ® MCM 53.50401 Cremophor ® RH 40 10.00 75 Povidone K 30 3.00 23 Lactic Acid 5.00 38Total Fill Weight 100.0% 750 Total Capsule Weight 1116

Samples from a batch of enteric soft capsules comprising the compositionshown in Table 28 were subject to two-stage dissolution experiments in aUSP Apparatus II with the parameters shown in Table 29. For theseexperiments, the capsule was introduced in to simulated gastric fluid,0.1 N HCl, pH 1.2, for 2 hours. After 2 hours, the capsule wastransferred to simulated intestinal fluid, phosphate buffer, pH 6.8. Theresults are shown in FIG. 14. The results show that the capsules retaintheir enteric properties for at least 2 hours in simulated gastric fluidat pH 1.2. The capsules began releasing BLS-11 within ˜10 minutes afterbeing transferred to simulated intestinal fluid, pH 6.8, and achieved100% dissolution after 120 minutes at pH 6.8.

TABLE 29 Two-stage Dissolution Analysis Parameters USP Apparatus IIAgitation Rate 100 RPM Temperature 37.0 ± 0.5° C. Media/Volume 0.1N HCl,pH 1.2, 500 mL Phosphate buffer, pH 6.8, 500 mL Sample Profile: Samplesobtained at 60 min and 120 min in 0.1N HCl Samples obtained at 10, 20,30, 45, 60, 120 min in phosphate buffer pH 6.8

Example 21 Method for Measurement of Fumarate Ester Particles SizeDistribution

Fumarate ester particles (dimethyl fumarate or mono methyl fumarate) inthe form of a dry powder were measured using a Malvern Mastersizer 2000instrument equipped with vacuum unit and air pressure followingmanufacturer instructions; see, e.g. The Mastersizer 2000 OperatorsGuide; MAN0247-2-0, Malvern Instruments Ltd. (1999), which isincorporated by reference herein for such teachings. Approximately 1.0gram of the test sample was introduced into the dry powder feeder andmeasured under the parameters shown in Table 28, and the volume sizedistribution and the volume mean diameter were determined. In oneaspect, described herein, the particle size distribution is expressed asa particle volume distribution and the mean particle size of thedistribution is expressed as a volume mean diameter.

TABLE 30 Particle Size Distribution Measurement Parameters AnalysisModel General Purpose Sensitivity Normal Particle RI 1.468 Vibrationfeed rate 60% Dispersive air pressure 1.3 bars Absorption 0.1Measurement time 6 seconds Measurement snaps 6,000 Background time 6seconds Background snaps 6,000 No. of measurements 1 per cycleObscuration 0.5% to 6.0%

Example 22 Clinical Study of Test Pharmaceutical Compositions ComprisingFumarate Esters Patient Population

Non-smoking male or females (n=24) within the age range of 18 to 65years, having a Body Mass Index (BMI) greater than or equal to 18.5kg/m² and less than or equal to 29.9 kg/m² and having given theirwritten informed consent were at the Period-I check-in of the study. Thepatient demographics and number of patients dosed is provided in Table31. They did not have any significant diseases or clinically significantabnormal findings during screening, medical history, physical andclinical examinations, laboratory evaluation, 12-lead ECG recording andvital sign measurement. Female volunteers had a negative pregnancy test.Volunteers who meet all the inclusion and exclusion criteria wereenrolled into the study.

All the subjects willing to participate in the study were screened nomore than 28 days before the first drug administration in order toassess their eligibility by satisfying all of the inclusion andexclusion criteria. During screening, the medical history of thesubjects was elicited and they underwent a general clinical examination,measurement of blood pressure, heart rate, body temperature, respiratoryrate, 12-Lead ECG, clinical laboratory evaluations, immunological testsfor HIV (Human Immunodeficiency Virus), HBsAg (Hepatitis B SurfaceAntigen) and HCV (Hepatitis C Virus), Alcohol screen, Nicotine screenand Screen for drugs of abuse. Urine pregnancy test was performed forall female subjects. Subjects were selected for inclusion in the studyno more than 28 days before the first drug administration.

TABLE 31 Study Population Inclusion Numbers and Parameter InformationNo. Planned for Inclusion 24 Enrolled and Checked-in 34 (Subject Nos.1001- 1024 and 10 standby subjects) Dosed Period-I 24 Period-II (7 dayslater) 23 Dismissed 01 Analyzed 23 Considered for statistical analysis23 Parameters Dosed Subjects (24) Completed Study (23) Age (years) 42.2± 12.81 42.2 ± 13.10 Height (cm) 171.14 ± 8.668  171.32 ± 8.817  Weight(kg) 75.05 ± 10.135 75.35 ± 10.258 BMI (kg/m²) 25.55 ± 2.280  25.60 ±2.320 

Study Methodology

The performed study was a randomized, pilot, two-way crossover,open-label, single-dose, fasting study, with a screening period of28-days prior to the first dose administration. In each study period, 19blood samples, including one pre-dose blood sample, were collected fromeach subject except for the subject who did not complete the study toanalyze the pharmacokinetic profile of the Test pharmaceuticalcomposition as well as the Reference pharmaceutical product.

Based on the elimination half-life of dimethyl fumarate, a washoutperiod of 7-days was kept in between the successive dosing days.Multiple blood samples were collected to assess the bioequivalencebetween the Test and the Reference product. For this study with acrossover design, each subject except for one dismissed subject receivedboth the products (Test Product-T and Reference Product-R) during thestudy. Hence, every subject acted as his own control and no separategroup of subjects was required to act as the control group. Subjectswere dosed according to the treatment sequence provided in Table 32. Theduration of the clinical part of the study was about 9 days (one dayprior to the drug administration in Period-I until the last studyprocedure in Period-II).

TABLE 32 Treatment Sequence Period-I Period-II Sequence 1 Treatment-R(Reference) Treatment-T (Test) Sequence 2 Treatment-T (Test) Treatment-R(Reference)

After an overnight fast of at least 10 hours, a single oral dose (240mg) of a Test pharmaceutical composition comprising dimethyl fumarate ora Reference dimethyl fumarate composition was administered to thesubjects in sitting posture with 240 mL of drinking water at ambienttemperature. The administration was as per the randomization scheduleand under open-label conditions.

Dosing water was measured and poured into individual containers beforedosing. The containers were then covered and allowed to remain atambient temperature until used. The drug was provided to the subjects inunit-dose containers. A visual inspection of each subject's mouth andhands was performed immediately after dosing to ensure drug ingestion.

During the first 4 hours post-dose, subjects were encouraged to stayawake, seated in an upright position, and allowed to rise undersupervision only for brief periods of time, in order to comply withstudy-related activities and to use the washroom. Subjects werepermitted to lie down for treatment of any adverse event.

No water ingestion was permitted from 1.0 hour pre-dose to 1.0 hourpost-dose, with the exception of the 240 mL of dosing water.

No food was allowed for at least 4 hours post-dose. Standardized mealswith beverages were provided to the subjects at the following times:between 4.5 and 5.5 hours post-dose; between 9.5 and 10.5 hourspost-dose; and at 13.5 hours post-dose.

All meals and beverages were free of alcohol, grapefruit products,xanthine, and caffeine and were identical between the study periods.

Safety was assessed from the screening period to the end of the study.It was assessed through clinical examinations, vital signs assessment,12-lead electrocardiogram (ECG), clinical laboratory parameters (e.g.,biochemistry, hematology, immunology, and urine analysis), pregnancytest (for female subjects), subjective symptomatology, and monitoring ofadverse events.

A total of 19 pharmacokinetic blood samples (6 mL each) were drawn ineach period according to the following schedule: 0 (pre-dose), and atintervals of 0.33, 0.67, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3,3.33, 3.68, 4, 4.5, 5, 6, and 8 hours post-dose.

The plasma samples of subjects were analyzed using a validated LC-MS/MSmethod for monomethyl fumarate. Calibration curve using an 8-pointcalibration curve standards, with concentrations ranging from 21.35ng/mL to 4967.75 ng/mL were used to determine the concentrations ofmonomethyl fumarate in the samples of various subjects.

Pharmacokinetic Parameter Calculations

The pharmacokinetic parameters were calculated from the drugconcentration versus time point by non-compartmental model usingWinNonlin Professional Software Version 5.3 (Pharsight Corporation, USA)for monomethyl fumarate. Statistical comparison of the pharmacokineticparameters of the two products (Test, Reference) was performed usingPROC MIXED of SAS® Version 9.3 (SAS Institute Inc., USA).

The maximum measured plasma concentration (C_(max)) and the time ofobserving the peak concentration (T_(max)) was taken directly from theplasma concentration versus time profile of the individual subjects.

Area under plasma concentration versus time curve (AUC_(0→τ)) in h·ng/mLfrom time zero to the last measurable concentration as calculated by thelinear trapezoidal rule.

Area under the plasma concentration versus time curve (AUC_(0→∞)) inh·ng/mL from time zero to infinity; whereAUC_(0→∞)=AUC_(0→τ)+C_(t)/λ_(z); C_(t) is the last measurableconcentration and λ_(z) is the terminal rate constant. The AUC_(0→∞) wasthe sum of measurable and extrapolated parts.

First order rate constants associated with the terminal (log-linear)portion of the curve were estimated via linear regression of time versuslog concentration. This parameter was calculated by linear least squaresregression analysis using last three or more non-zero plasmaconcentration values. The units of λ_(z) were hours⁻¹ (1/h).

The terminal half-life was calculated using the formula: 0.693/λ_(z).The unit of t_(1/2) was hour (h).

The residual area in percentage was determined by the formula:

[(AUC _(0→∞) −AUC _(0→τ))/AUC _(0→∞)]×100.

The pharmacokinetic parameters of monomethyl fumarate for Test Product-Tand Reference Product-R are summarized in Table 33. The mean plasmaconcentration versus time curve over eight hours is shown in FIG. 15.

TABLE 33 Pharmacokinetic Parameters of Monomethyl Fumarate; TestProduct-T and Reference Product-R Mean ± SD (Un-transformed data)Pharmacokinetic Parameters Test Product-T Reference Product-R T_(max)(h) 2.5 (1-5) 2.5 (1-5) C_(max) (ng/mL) 1321.3 ± 618.9   1174.7 ± 433.9 AUC_(0→τ) h · ng/mL 1818.415 ± 532.5886  1907.405 ± 525.7948 AUC_(0→∞)1919.247 ± 533.8147*  2119.693 ± 688.1376{circumflex over ( )} λ_(z)(1/h) 1.323 ± 0.3573*  1.103 ± 0.3930{circumflex over ( )} t_(1/2) (h)0.563 ± 0.1586*  0.864 ± 0.8508{circumflex over ( )} Residual Area inPercentage 1.799 ± 1.0276*  6.481 ± 14.0612{circumflex over ( )} *n = 20{circumflex over ( )}n = 22

Statistical Methods

Descriptive statistics were calculated and reported for allpharmacokinetic parameters of monomethyl fumarate. ANOVA, power, andratio analysis for ln-transformed pharmacokinetic parameters C_(max),AUC_(0→τ), and AUC_(0→∞) were calculated and reported for monomethylfumarate. The 90% confidence interval for the ratio of the geometricleast-squares means were calculated for the ln-transformedpharmacokinetic parameters, C_(max), AUC_(0→τ), and AUC_(0→∞) formonomethyl fumarate. All statistical analyses for Monomethyl Fumaratewere performed using PROC MIXED of SAS® Version 9.3 (SAS Institute Inc.,USA).

The relative bioavailability analysis (e.g., geometric least squaresmeans, ratios, 90% confidence interval, intra subject CV, and power) ofTest Product-T versus Reference Product-R for monomethyl fumarate issummarized in Table 34.

TABLE 34 Relative Bioavailability Results for Monomethyl Fumarate (n =23) Geometric Least Squares Means Intra Test Reference Ratio 90%Confidence Subject Parameters Product-T Product-R (T/R)% Interval CV (%)Power (%) C_(max) 1189.160 1102.137 107.9 92.04-126.49 32.1 75.3AUC_(0→τ) 1747.744 1847.786 94.6 87.59-102.14 15.2 99.8 AUC_(0→∞)1875.657* 2034.147{circumflex over ( )} 92.2 85.17-99.82  14.3 99.7 *n =20 {circumflex over ( )}n = 22

What is claimed is:
 1. A method of treating or reducing symptoms of amultiple sclerosis or psoriasis in a subject, the method comprisingadministering an oral pharmaceutical composition comprising an immediatereleasing single phase non-aqueous liquid vehicle and a fumarate esteror a salt thereof having the formula:

wherein R₁ and R₂, may be the same or different, and independentlyrepresent hydrogen or methyl.
 2. The composition of claim 1, wherein R₁is hydrogen.
 3. The composition of claim 1, wherein R₁ is methyl.
 4. Thecomposition of claim 1, wherein R₂ is methyl.
 5. The composition ofclaim 1, wherein R₁ is hydrogen and R₂ is methyl.
 6. The composition ofclaim 1, wherein R₁ is methyl and R₂ is methyl.
 7. The method of claim1, wherein the fumarate ester is:

or a salt thereof.
 8. The method of claim 1, wherein the fumarate esteris:


9. The method of claim 1, wherein the composition comprises about 60 mgto about 200 mg of the fumarate ester or salt thereof.
 10. The method ofclaim 1, wherein the composition comprises about 90 mg to about 100 mgor about 100 mg to about 200 mg of the fumarate ester or salt thereof.11. The method of claim 1, wherein the liquid vehicle comprises mono-and di-glycerides, polyvinylpyrrolidone, and polyoxyl 40 hydrogenatedcastor oil.
 12. The method of claim 1, wherein the compositioncomprises: about 30% to about 40% by weight of the fumarate ester orsalt thereof; and about 55% to about 65% by weight of the liquidvehicle.
 13. The method of claim 1, wherein the composition comprisesabout 5% by weight of lactic acid.
 14. The method of claim 1, whereinthe composition is encapsulated in a capsule.
 15. The method of claim1812, wherein the capsule provides delayed release of the fumarate esteror salt thereof.
 16. The method of claim 1, wherein upon administrationto a subject, the composition activates a nuclear factorerythroid-derived 2-like (Nrf2) dependent pathway.